Abstract
Development of therapeutic resistance limits the efficacy of current cancer treatment. Understanding the molecular basis for therapeutic resistance should facilitate the identification of actionable targets and development of new combination therapies for cancer patients. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. The unveiling point mutations within the kinase domain, gene amplification or overexpression, or modification of signaling pathway have been implicated in drug resistance. In the review, we will describe different currently developed strategies that have the potential to overcome drug resistance in different types of cancer therapies and facilitate prolonged anticancer effects of the first-line therapies. The knowledge obtained from these studies will allow to design better strategies to offer significant challenges on the path towards superior cancer treatment.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- AIO:
-
Arbeitsgemeinschaft Internistische Onkologie
- AIP5:
-
Apoptosis inhibitory protein 5
- ATP:
-
Adenosine triphosphate
- Bcl-2:
-
B-cell lymphoma 2
- BCR-ABL:
-
Breakpoint cluster region-Abelson
- BIRC2:
-
Baculoviral IAP repeat-containing 2
- B-Raf:
-
v-Raf murine sarcoma viral oncogene homolog B
- CBL:
-
Casitas B-lineage lymphoma
- Cdk:
-
Cyclin-dependent kinase
- c-FLIP:
-
Caspase 8 and FAS-associated protein with death domain-like apoptosis regulator
- CI:
-
Confidence interval
- CR:
-
Complete response
- CREB:
-
cAMP-responsive element binding protein
- CRTC2:
-
CREB-regulated transcription coactivator 2
- CXCR4:
-
C-S-C chemokine receptor type 4
- CYP3A4:
-
Cytochrome P450 3A4
- DDR1:
-
Discoidin domain receptor 1
- DFS:
-
Disease free survival
- EGFR:
-
Epidermal growth factor receptor
- ErbB2:
-
Epidermal growth factor receptor II (Her 2)
- EREG:
-
Epiregulin
- EZH2:
-
Enhancer of zeste homolog 2
- FGF2:
-
Fibroblast growth factor
- FLT1:
-
FMI-like tyrosine kinase 1
- FLT3:
-
FMS-like tyrosine kinase 3
- FOLFIRI:
-
Folinic acid, Fluorouracil and Irinotecan
- FOLFOX:
-
Folinic acid (FA)-Fluorouracil (5FU)-Oxaliplatin (OX)
- FOXO3a:
-
Forkhead box O3 isoform a
- GDNFR:
-
Glial-cell-line-derived neurotrophic factor receptor
- GSK:
-
Glycogen synthase kinase
- H2AFX:
-
H2A histone family-member X
- HR:
-
Hazard ratio
- HRG:
-
Heregulin HGFR hepatocyte growth factor receptor
- IGFR 1:
-
Insulin-like growth factor receptor 1
- IgG:
-
Immunoglobulin G
- IRS-1:
-
Insulin receptor substrate 1
- JAK:
-
Janus kinase
- KDR:
-
Kinase insert domain-containing receptor tyrosine kinase
- LA-HNSCC:
-
Locally advanced head and neck squamous cell carcinoma
- LOH:
-
Loss of heterozygosity
- m-AMSA:
-
4′-(9-Acridinylamino)methanesulfon-m-aniside
- MET:
-
Mesenchymal epithelial transition
- MMR:
-
DNA mismatch repair
- MR:
-
Minor response
- MSI:
-
Microsatellite instability
- MTD:
-
Maximum tolerated dose
- p27kip1 (p27):
-
A cyclin-dependent kinase inhibitor
- p70S6K:
-
(p70) S6 kinase
- PDGFR:
-
Platelet-derived growth factor receptor
- PIK3CA:
-
Phosphatidylinositol 3-kinase catalytic subunit
- PLGF:
-
Placental growth factor
- PR:
-
Partial response
- RR:
-
Relative risk
- SCFR:
-
Stem cell factor receptor
- SD:
-
Stable disease
- SDF-1:
-
Stromal-derived-factor-1
- siRNA:
-
Small interfering RNA
- Skp2:
-
S-phase kinase-associated protein 2
- TAM:
-
Tyro3/Axl/Mer
- TGF-α:
-
Transforming growth factor α
- TOPO-II:
-
Topoisomerase-II
- TRIAP1:
-
TP53 regulated inhibitor of apoptosis 1
- VEGFR:
-
Vascular endothelial growth factor receptors
References
Levitzki A, Mishani E. Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem. 2006;75:93–109.
Crean S, Boyd DM, Sercus B, Lahn M. Safety of multi-targeted kinase inhibitors as monotherapy treatment of cancer: a systematic review of the literature. Curr Drug Saf. 2009;4:143–54.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40.
Blanke CD, Corless CL. State-of-the art therapy for gastrointestinal stromal tumors. Cancer Invest. 2005;23:274–80.
Ravegnini G, Nannini M, Sammarini G, et al. Personalized medicine in gastrointestinal stromal tumor (GIST): clinical implications of the somatic and germline DNA analysis. Int J Mol Sci. 2015;16:15592–608.
Moy B, Goss PE. Lapatinib: current status and future directions in breast cancer. Oncologist. 2006;11:1047–57.
Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem. 2000;69:373–98.
Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355–65.
Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2002;103:211–25.
Hunter T. Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 2009;21:140–6.
Edelman AM, Blumenthal DK, Krebs EG. Protein serine/threonine kinases. Annu Rev Biochem. 1987;56:567–613.
Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61:203–12.
Yarden Y, Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–78.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–34.
Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19:5548–57.
Knuutila S, Bjorkqvist AM, Autio K, et al. DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am J Pathol. 1998;152:1107–23.
Collett MS, Erikson RL. Protein kinase activity associated with the avian sarcoma virus src gene product. Proc Natl Acad Sci U S A. 1978;75:2021–4.
Stehelin D. The transforming gene of avian tumor viruses. Pathol Biol (Paris). 1976;24:513–5.
Hunter T. Protein phosphorylated by the RSV transforming function. Cell. 1980;22:647–8.
Hunter T, Sefton BM. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Natl Acad Sci U S A. 1980;77:1311–5.
Varmus H, Bishop JM. Biochemical mechanisms of oncogene activity: proteins encoded by oncogenes. Introduction. Cancer Surv. 1986;5:153–8.
Downward J, Yarden Y, Mayes E, et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984;307:521–7.
Ullrich A, Coussens L, Hayflick JS, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature. 1984;309:418–25.
Chazin VR, Kaleko M, Miller AD, Slamon DJ. Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene. 1992;7:1859–66.
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.
DiGiovanna MP, Stern DF, Edgerton SM, Whalen SG, Moore 2nd D, Thor AD. Relationship of epidermal growth factor receptor expression to ErbB-2 signaling activity and prognosis in breast cancer patients. J Clin Oncol. 2005;23:1152–60.
Tsatsanis C, Spandidos DA. Oncogenic kinase signaling in human neoplasms. Ann N Y Acad Sci. 2004;1028:168–75.
Hunter T. A thousand and one protein kinases. Cell. 1987;50:823–9.
Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–9.
Hunter T. Signaling-2000 and beyond. Cell. 2000;100:113–27.
Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A. Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res. 1990;50:1550–8.
Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989;9:1165–72.
Sasaki T, Hiroki K, Yamashita Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Biomed Res Int. 2013;2013:546318.
Bazley LA, Gullick WJ. The epidermal growth factor receptor family. Endocr Relat Cancer. 2005;12(Suppl):S17–27.
Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.
Goldberg RM. Cetuximab. Nat Rev Drug Discov. 2005;Suppl:S10–1.
Yang B, Lum P, Chen A, et al. Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab. Clin Pharmacokinet. 2010;49:729–40.
Giannopoulou E, Antonacopoulou A, Matsouka P, Kalofonos H. Autophagy: novel action of panitumumab in colon cancer. Anticancer Res. 2009;29:5077–82.
Keating G. Panitumumab: a review of its use in metastatic colorectal cancer. Drugs 2010;0:1059–78.
Hocking CM, Price TJ. Panitumumab in the management of patients with KRAS wild-type metastatic colorectal cancer. Therap Adv Gastroenterol. 2014;7:20–3.
Robinson KW, Sandler AB. EGFR tyrosine kinase inhibitors: difference in efficacy and resistance. Curr Oncol Rep. 2013;15:396–404.
O’Donnell P, Ferguson J, Shyu J, et al. Analytic performance studies and clinical reproducibility of a real-time PCR assay for the detection of epidermal growth factor receptor gene mutations in formalin-fixed paraffin-embedded tissue specimens of non-small cell lung cancer. BMC Cancer. 2013;13:210.
Dragovich T, McCoy S, Fenoglio-Preiser CM, et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006;24:4922–7.
Wainberg ZA, Lin LS, DiCarlo B, et al. Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. Br J Cancer. 2011;105:760–5.
Schilder RJ, Sill MW, Lee YC, Mannel R. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. Int J Gynecol Cancer. 2009;19:929–33.
Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009;27:5788–93.
Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: Reasons for phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20:2072–9.
Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci. 2014;15:13768–801.
Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001;1:85–94.
Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21:6255–63.
Food and Drug Administration. FDA labelling information [online]. (2007). http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation
Fry DW, Bridges AJ, Denny WA, et al. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci U S A. 1998;95:12022–7.
Smaill JB, Palmer BD, Rewcastle GW, et al. Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor. J Med Chem. 1999;42:1803–15.
Djerf EA, Trinks C, Abdiu A, Thunell LK, Hallbeck AL, Walz TM. ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839). Melanoma Res. 2009;19:156–66.
Djerf Severinsson EA, Trinks C, Gréen H, et al. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem Biophys Res Commun. 2011;414:563–8.
Ako E, Yamashita Y, Ohira M, et al. The pan-erbB tyrosine kinase inhibitor CI-1033 inhibits human esophageal cancer cells in vitro and in vivo. Oncol Rep. 2007;17:887–93.
Nyati MK, Maheshwari D, Hanasoge S, et al. Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo. Clin Cancer Res. 2004;10:691–700.
Slichenmyer WJ, Elliott WL, Fry DW. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol. 2001;28:80–5.
Rixe O, Franco SX, Yardley DA, et al. A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer. Cancer Chemother Pharmacol. 2009;64:1139–48.
Janne PA, von Pawel J, Cohen RB, et al. Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non small cell lung cancer. J Clin Oncol. 2007;25:3936–44.
Irwin ME, Nelson LD, Santiago-O’Farrill JM, et al. Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in Philadelphia chromosome-positive acute lymphoblastic leukemia. PLoS One. 2013;8, e70608.
Fabian MA, Biggs 3rd WH, Treiber DK, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005;23:329–36.
Dorsey K, Agulnik M. Promising new molecular targeted therapies in head and neck cancer. Drugs. 2013;73:315–25.
Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007;67:11924–32.
Gonzales AJ, Hook KE, Althaus IW, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2008;7:1880–9.
Janne PA, Boss DS, Camidge DR, et al. Phase I dose-escalation study of the pan-HER inhibitor, PF-00299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011;17:1131–9.
Takahashi T, Boku N, Murakami H, et al. Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors. Invest New Drugs. 2012;30:2352–63.
Ramalingam SS, Jänne PA, Mok TS, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:1369–78.
Park K, Heo DS, Cho B, et al. PF-00299804 (PF299) in Asian patients (pts) with non-small cell lung cancer (NSCLC) refractory to chemotherapy (CT) and erlotinib (E) or gefitinib (G): a phase (P) I/II study. J Clin Oncol. 2010;28 Suppl:abstract 7599.
Boyer MJ, Blackhall FH, Park K, et al. Efficacy and safety of PF299804 versus erlotinib: a global randomized phase 2 trial in patients with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy (CT). Oral presentation at: the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, USA, 2010; June 4–8.
Kris MG, Mok T, Ou SH, et al. First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, for patients with EGFR-mutant lung cancers. J Clin Oncol. 2012:30 Suppl: abstract 7530.
Ruiz-Garcia A, Janne PA, Park K, et al. EGFR status and daily dose: Effect on tumor growth inhibition in cancer patients treated with dacomitinib (PF-00299804). J Clin Oncol. 2012;30 Suppl: abstract e18093.
Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008;27:4702–11.
Metro G, Crinò L. The LUX-Lung clinical trial program of afatinib for non-small-cell lung cancer. Expert Rev Anticancer Ther. 2011;11:673–82.
clinicaltrials.gov. LUX-Breast 2; Afatinib in HER2 (Human Epidermal Growth Factor Receptor)-treatment failures NCT01271725 (2011–2016).
clinicaltrials.gov. 6 weeks treatment of locally advanced breast cancer with BIBW 2992 (Afatinib) or Lapatinib or Trastuzumab NCT00826267. http://www.clinicaltrials.gov/ct2/show/NCT00826267. Accessed 2 Feb 2012.
clinicaltrials.gov. Afatinib (BIBW2992) in HER2-overexpressing inflammatory breast cancer NCT013254 (2011–2016).
clinicaltrials.gov. LUX-Breast 1: BIBW 2992 (Afatinib) in HER2-positive metastatic breast cancer patients after one prior herceptin treatment NCT01125566 (2010–2016).
Rabindran SK, Discafani CM, Rosfjord EC, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Can Res. 2004;64:3958–65.
Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28:1301–7.
clinicaltrials.gov. Study evaluating the effects of neratinib after adjuvant trastuzumab in women with early stage breast cancer (ExteNET) NCT00878709. http://clinicaltrials.gov/ct2/show/NCT00878709. Accessed 1 Apr 2012.
clinicaltrials.gov. A phase 1/2 study of HKI-272 (Neratinib) in combination with paclitaxel (taxol) in subjects with solid tumors and breast cancer NCT00445458. http://clinicaltrials.gov/ct2/show/NCT00445458. Accessed 1 Apr 2012.
clinicaltrials.gov. A phase 1/2 Study Of HKI-272 (Neratinib) in combination with trastuzumab (herceptin) in subjects with advanced breast cancer NCT00398567. http://clinicaltrials.gov/ct2/show/NCT00398567. Accessed 1 Apr 2012.
clinicaltrials.gov. Study evaluating neratinib plus paclitaxel vs trastuzumab plus paclitaxel in ErbB-2 positive advanced breast cancer (NEFERTT) NCT00915018. http://clinicaltrials.gov/ct2/show/NCT00915018. Accessed 1 Apr 2012.
clinicaltrials.gov. Study evaluating neratinib versus lapatinib plus capecitabine for ErbB2 positive advanced breast cancer NCT00777101. http://clinicaltrials.gov/ct2/show/NCT00777101. Accessed 1 Apr 2012.
Berger C, Krengel U, Stang E, Moreno E, Madshus IH. Nimotuzumab and cetuximab block ligand-independent EGF receptor signaling efficiently at different concentrations. J Immunother. 2011;34:550–5.
Solomon MT, Selva IC, Figueredo J, et al. Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial. BMC Cancer. 2013;13:299.
Heinrich MC, Griffith D, McKinley A, et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res. 2012;18:4375–84.
Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res. 2002;62:3729–35.
Dong J, Grunstein J, Tejada M, et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. Embo J. 2004;23:2800–10.
Pietras K, Pahler J, Bergers G, Hanahan D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 2008;5, e19.
Puputti M, Tynninen O, Sihto H, et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res. 2006;4:927–34.
Ostman A, Heldin CH. PDGF receptors as targets in tumor treatment. Adv Cancer Res. 2007;97:247–74.
Jain RK, Lahdenranta J, Fukumura D. Targeting PDGF signaling in carcinoma-associated fibroblasts controls cervical cancer in mouse model. PLoS Med. 2008;5, e24.
Thomson S, Petti F, Sujka-Kwok I, Epstein D, Haley JD. Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. Clin Exp Metastasis. 2008;25:843–54.
Ehnman M, Missiaglia E, Folestad E, et al. Distinct effects of ligand-induced PDGFRα and PDGFRβ signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments. Cancer Res. 2013;73:2139–49.
Hayashi Y, Bardsley MR, Toyomasu Y, et al. Platelet-derived growth factor receptor-α regulates proliferation of gastrointestinal stromal tumor cells with mutations in KIT by stabilizing ETV1. Gastroenterology. 2015;149:420–32.
Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res. 2012;18:1855–62.
Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. 2011;437:199–213.
Taylor JG, Cheuk AT, Tsang PS, et al. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. J Clin Invest. 2009;119:3395–407.
Tanner Y, Grose RP. Dysregulated FGF signalling in neoplastic disorders. Semin Cell Dev Biol. 2015; pii: S1084-9521(15)00209-8.
Gelsi-Boyer V, Orsetti B, Cervera N, Finetti P, et al. Comprehensive profiling of 8p11-12 amplification in breast cancer. Mol Cancer Res. 2005;3:655–67.
Turner N, Lambros MB, Horlings HM, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;20:2013–23.
Mohammadi M, Froum S, Hamby JM, et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998;17:5896–904.
Koziczak M, Holbro T, Hynes NE. Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins. Oncogene. 2004;23:3501–8.
Buchler P, Reber HA, Roth MM, Shiroishi M, Friess H, Hines OJ. Target therapy using a small molecule inhibitor against angiogenic receptors in pancreatic cancer. Neoplasia. 2007;9:119–27.
Dey JH, Bianchi F, Voshol J, Bonenfant D, Oakeley EJ, Hynes NE. Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis. Cancer Res. 2010;70:4151–62.
Sarker D, Molife R, Evans TR, et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2008;14:2075–81.
Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun. 2004;314:409–14.
Dean M, Park M, Liu W, et al. The human met oncogene is related to the tyrosine kinase oncogenes. Nature. 1985;318:385–8.
Boon EM, van der Neut R, van de Wetering M, Clevers H, Pals ST. Wnt signaling regulates expression of the receptor tyrosine kinase met in colorectal cancer. Cancer Res. 2002;62:5126–8.
Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov. 2008;7:504–16.
Tsao MS, Yang Y, Marcus A, Liu N, Mou L. Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non-small-cell lung cancer. Hum Pathol. 2001;32:57–65.
Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer. 2002;2:289–300.
Love CA, Harlos K, Mavaddat N, et al. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat Struct Biol. 2003;10:843–8.
Gherardi E, Love CA, Esnouf RM, Jones EY. The sema domain. Curr Opin Struct Biol. 2004;14:669–78.
Kong-Beltran M, Stamos J, Wickramasinghe D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell. 2004;6:75–84.
Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. EMBO J. 2004;23:2325–35.
Wickramasinghe D, Kong-Beltran M. Met activation and receptor dimerization in cancer: a role for the Sema domain. Cell Cycle. 2005;4:683–5.
Olivero M, Valente G, Bardelli A, et al. Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family. Int J Cancer. 1999;82:640–3.
Schmidt L, Junker K, Nakaigawa N, et al. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene. 1999;18:2343–50.
Giordano S, Maffe A, Williams TA, et al. Different point mutations in the met oncogene elicit distinct biological properties. FASEB J. 2000;14:399–406.
Lee JH, Han SU, Cho H, et al. A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene. 2000;19:4947–53.
Ma PC, Tretiakova MS, MacKinnon AC, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer. 2008;47:1025–37.
Seiwert TY, Jagadeeswaran R, Faoro L, et al. The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res. 2009;69:3021–31.
Stella GM, Benvenuti S, Gramaglia D, et al. MET mutations in cancers of unknown primary origin (CUPs). Hum Mutat. 2011;32:44–50.
Lutterbach, Zeng Q, Davis LJ, et al. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res. 2007;67:2081–8.
Peschard P, Fournier TM, Lamorte L, et al. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol Cell. 2001;8:995–1004.
Zeng ZS, Weiser MR, Kuntz E, et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 2008;265:258–69.
Cappuzzo F, Jänne PA, Skokan M, et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol. 2009;20:298–304.
Go H, Jeon YK, Park HJ, Sung SW, Seo JW, Chung DH. High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer. J Thorac Oncol. 2010;5:305–13.
Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF- 2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007;67:4408–17.
Corso S, Migliore C, Ghiso E, De Rosa G, Comoglio PM, Giordano S. Silencing the MET oncogene leads to regression of experimental tumors and metastases. Oncogene. 2008;27:684–93.
Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009;15:2207–14.
Jin H, Yang R, Zheng Z, et al. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res. 2008;68:4360–8.
NCT01418222 and Genentech. Randomized, double-blind, phase II study of FOLFOX/Bevacizumab with onartuzumab (MetMAb) versus placebo as first-line treatment for patients with metastatic colorectal cancer. 2011–2016; From http://clinicaltrials.gov/show/NCT01418222.
Bendell JC, Ervin TJ, Gallinson D, et al. Treatment rationale and study design for a randomized, double-blind, placebo-controlled phase II study evaluating onartuzumab (MetMAb) in combination with bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal cancer. Clin Colorectal Cancer. 2013;12:218–22.
Martens T, Schmidt NO, Eckerich C, et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res. 2006;12:6144–52.
Vigna E, Pacchiana G, Mazzone M, et al. Active cancer immunotherapy by anti-Met antibody gene transfer. Cancer Res. 2008;68:9176–83.
Gordon MS, Sweeney CS, Mendelson DS, et al. Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors. Clin Cancer Res. 2010;16:699–710.
Wen PY, Schiff D, Cloughesy TF, et al. A phase II study evaluating the efficacy and safety of AMG102 (rilotumumab) in patients with recurrent glioblastoma. Neuro Oncol. 2011;13:437–46.
Munshi N, Jeay S, Li Y, et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010;9:1544–53.
Eathiraj S, Palma R, Volckova E, et al. Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal-epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197. J Biol Chem. 2011;286:20666–76.
Schiller JH, Akerley WL, Brugge W, et al. Results from ARQ 197-209: a global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(18s), LBA7502.
NCT01611857. A Phase I/II Trial of the c-Met inhibitor, tivantinib, in combination with FOLFOX for the treatment of patients with advanced solid tumors (phase I) and previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach (phase II). 2012: From http://clinicaltrials.gov/ct2/show/NCT01611857.
Basilico C, Pennacchietti S, Vigna E, et al. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin Cancer Res. 2013;19:2381–92.
Katayama R, Aoyama A, Yamori T, et al. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res. 2013;73:3087–96.
NCT00788957 and Amgen. Panitumumab combination study with AMG 102 or AMG 479 in Wild-type KRAS mCRC. 2008; From http://clinicaltrials.gov/ct2/show/NCT00788957.
Bladt F, Faden B, Friese-Hamim M, et al. EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors. Clin Cancer Res. 2013;19:2941–51.
Medova M, Pochon B, Streit B, et al. The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants. Mol Cancer Ther. 2013;12:2415–24.
Humbert M, Medova M, Aebersold DM, et al. Protective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells. Biochem Biophys Res Commun. 2013;431:264–9.
Scorsone K, Zhang L, Woodfield SE, Hicks J, Zage PE. The novel kinase inhibitor EMD1214063 is effective against neuroblastoma. Investig New Drugs. 2014;32:815–24.
Graham DK, Salzberg DB, Kurtzberg J, et al. Ectopic expression of the proto-oncogene mer in pediatric T-cell acute lymphoblastic leukemia. Clin Cancer Res. 2006;12:2662–9.
Linger RMA, Keating AM, Earp HS, Graham DK. TAM receptor tyrosine kinases: Biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35–83.
Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of AXL kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70:1544–54.
Wnuk-Lipinska K, Gausdal G, Sandal T, et al. Selective small molecule AXL inhibitor BGB324 overcomes acquired drug resistance in non-small cell lung carcinoma models. Clin Cancer Res. 2014;20:B30.
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.
Morgan B, Thomas AL, Drevs J, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol. 2003;21:3955–64.
Jost LM, Gschwind HP, Jalava T, et al. Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients. Drug Metab Dispos. 2006;34:1817–28.
Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60:2178–89.
Nakamura K, Taguchi E, Miura T, et al. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res. 2006;66:9134–42.
Mayer EL, Scheulen ME, Beckman J, et al. A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer. Breast Cancer Res Treat. 2013;140:331–9.
Eskens FA, de Jonge MJ, Bhargava P, et al. Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin Cancer Res. 2011;17:7156–63.
Batchelor TT, Duda DG, di Tomaso E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28:2817–23.
Wick W, Wick A, Weiler M, Weller M. Patterns of progression in malignant glioma following anti‐VEGF therapy: perceptions and evidence. Curr Neurol Neurosci Rep. 2011;11:305–12.
Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan‐VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11:83–95.
Rahman R, Smith S, Rahman C, Grundy R. Antiangiogenic therapy and mechanisms of tumor resistance in malignant glioma. J Oncol. 2010;2010:251231.
Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin‐ 1, and matrix metalloproteinases. Cancer Cell. 2004;6:553–63.
Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65:4389–400.
Takeda M, Arao T, Yokote H, et al. AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin Cancer Res. 2007;13:3051–7.
Siemann DW, Brazelle WD, Jurgensmeier JM. The vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor cediranib (Recentin; AZD2171) inhibits endothelial cell function and growth of human renal tumor xenografts. Int J Radiat Oncol Biol Phys. 2009;73:897–903.
Medinger M, Esser N, Zirrgiebel U, Ryan A, Jurgensmeier JM, Drevs J. Antitumor and antiangiogenic activity of cediranib in a preclinical model of renal cell carcinoma. Anticancer Res. 2009;29:5065–76.
Dietrich J, Wang D, Batchelor TT. Cediranib: profile of a novel antiangiogenic agent in patients with glioblastoma. Expert Opin Investig Drugs. 2009;18:1549–57.
Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16–24.
Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516–24.
Motzer RJ, Hutson TE, Tomczak P, et al. Phase III ran domized trial of sunitinib malate (SU11248) versus interferon alfa (IFN-a) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2006;24 (Suppl; late breaking abstract 3).
Casali PG, Garrett CR, Blackstein ME, et al. Updated results from a phase III trial of sunitinib in GIST patients (pts) for whom imatinib (IM) therapy has failed due to resistance or intolerance. J Clin Oncol. 2006; 24 (Suppl; abstr 9513).
Demetri G, van Oosterom AT, Garrett C, et al. Improved survival and sustained clinical benefit with SU11248 (SU) in pts with GIST after failure of imatinib mesylate (IM) therapy in a phase III trial. 2006 Gastrointestinal Cancers Symposium 2006; Abstract No: 8.
George S, Casali PG, Blay J, et al. Phase II study of sunitinib administered in a continuous daily dosing regimen in patients (pts) with advanced GIST. J Clin Oncol. 2006;24 (Suppl; abstr 9532) 87.
Socinski MA, Novello S, Sanchez JM, et al. Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): preliminary results of a multicenter phase II trial. J Clin Oncol. 2006;24 (Suppl; abstr 241):88.
Kulke M, Lenz HJ, Meropol NJ, et al. A phase 2 study to evaluate the efficacy and safety of SU11248 in patients (pts) with unresectable neuroendocrine tumors (NETs). J Clin Oncol. 2005;23 (Suppl; abstr 4008).
Sridhar SS, Hedley D, Siu LL. Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther. 2005;4:677–85.
Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractoryn solid tumors. J Clin Oncol. 2005;23:965–72.
Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505–12.
Ratain MJ, Eisen T, Stadler WM, et al. Final findings from a Phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol. 2005;23 (Suppl; abstr 4544).
Escudier B, Szczylic C, Eisen T, et al. Randomized Phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol. 2005;23 (Suppl; late breaking abstract 4510).
Eisen T, Bukowski RM, Staehler M, et al. Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): impact of crossover on survival. J Clin Oncol. 2006;24 (Suppl; abstr 4524).
Perez-Soler R. Can rash associated with HER1/EGFR inhi bition be used as a marker of treatment outcome? Oncology (Williston Park). 2003;17:23–8.
Strumberg D, Awada A, Hirte H, et al. Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? Eur J Cancer. 2006;42:548–56.
Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73–4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129:245–55.
Grothey A, Van Cutsem E, Sobrero A, et al. CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer: an international, multicentre, prospective, randomised, placebo controlled phase 3 trial (CORRECT). Lancet. 2013;381:303–12.
Schmieder R, Hoffmann J, Becker M, et al. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer). Intern J Cancer. 2014;135:1487–96.
Tang R, Kain T, Herman J, Seer T. Durable response using regorafenib in an elderly patient with metastatic colorectal cancer: case report. Cancer Manag Res. 2015;7:357–60.
Parikh SS, Mehta HH, Desai BI. Advances in development of bevacizumab, a humanized antiangiogenic therapeutic monoclonal antibody targeting VEGF in cancer cells. Int J Pharm Biomed Sci. 2012;3:155–63.
Tabrizi M, Roskos LK. xposure–response relationships for therapeutic biologic products. In: Meibohm B, editor. Pharmacokinetics and pharmacodynamics of biotech drugs. Principles and case studies in drug development. Weinheim: Wiley-VCH; 2006. p. 295–327.
Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005;65:671–80.
Schutz FA, Je Y, Azzi GR, Nguyen PL, Choueiri TK. Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes. Ann Oncol. 2011;22:1404–12.
Economopoulou E, Kotsakis A, Kapiris I, Kentepozidis N. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015;15:133–43.
Mirone G, Shukla A, Marfe G. Signaling mechanisms of resistance to EGFR- and Anti-Angiogenic Inhibitors cancer. Crit Rev Oncol Hematol. 2016;97:85–95.
Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99:11393–8.
Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391–400.
Kim ES, Serur A, Huang J, Manley CA, et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci U S A. 2002;99:11399–404.
Rudge JS, Holash J, Hylton D. Inaugural article: VEGF trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A. 2007;104:18363–70.
Gomez-Manzano C, Holash J, Fueyo J. VEGF Trap induces antiglioma effect at different stages of disease. Neuro Oncol. 2008;10:940–5.
Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin based regimen. J Clin Oncol. 2012;30:3499–506.
Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: Preclinical data and clinical implications. Lancet Oncol. 2012;13:e23–31.
Wu JY, Wu SG, Yang CH, et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res. 2008;14:4877–82.
Greulich H, Chen TH, Feng W, et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2005;2, e313.
Inukai M, Toyooka S, Ito S, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res. 2006;66:7854–8.
Tokumo M, Toyooka S, Ichihara S, et al. Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer. Lung Cancer. 2006;53:117–21.
Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26:2442–9.
Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77–88.
Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.
Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements. A new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 2009;4:1450–4
Selinger CI, Rogers TM, Russell PA, et al. Testing for ALK rearrangement in lung adeno- carcinoma-a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol. 2013;26:1545–53.
Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14:4275–83.
Choi YL, Takeuchi K, Soda M, et al. Identification of novel isoform of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res. 2008;68:4971–6.
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.
Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8:823–59.
Méndez M, Custodio A, Provencio M. New molecular targeted therapies for advanced non-small-cell lung cancer. J Thorac Dis. 2011;3:30–56.
Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013;31:3987–96.
Costa DB, Halmos B, Kumar A, et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 2007;4:1669–79. discussion 1680.
Cragg MS, Kuroda J, Puthalakath H, et al. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med. 2007;4:1681–9. discussion 1690.
Gong Y, Somwar R, Politi K, et al. Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med. 2007;4, e294.
Faber AC, Corcoran RB, Ebi H, et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov. 2011;1:352–65.
Ng KP, Hillmer AM, Chuah CT, et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med. 2012;18:521–8.
Ercan D, Zejnullahu K, Yonesaka K, et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene. 2010;29:2346–56.
Borras E, Jurado I, Hernan I, et al. Clinical pharmacogenomic testing of KRAS, BRAF and EGFR mutations by high resolution melting analysis and ultra-deep pyrosequencing. BMC Cancer. 2011;11:406.
Provencio M, Garcia-Campelo R, Isla D, de Castro J. Clinical molecular factors predicting response and survival for tyrosine-kinase inhibitors. Clin Transl Oncol. 2009;11:428–36.
Rosell R, Ichinose Y, Taron M, et al. Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer. Lung Cancer. 2005;50:25–33.
Rosell R, Moran T, Cardenal F, et al. Predictive biomarkers in the management of EGFR mutant lung cancer. Ann N Y Acad Sci. 2010;1210:45–52.
Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070–5.
Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472–82.
Lovly CM, Pao W. Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. Sci Transl Med. 2012;4:120.
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.
Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17.
Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011;108:7535–40.
Guix M, Faber AC, Wang SE, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118:2609–19.
Yano S, Wang W, Li Q, et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 2008;68:9479–87.
Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 2003;63:7345–55.
Miller CT, Lin L, Casper AM, et al. Genomic amplification of MET with boundaries within fragile site FRA7G and upregulation of MET pathways in esophageal adenocarcinoma. Oncogene. 2006;25:409–18.
Smolen GA, Sordella R, Muir B, et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci U S A. 2006;103:2316–21.
Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2012;2:922–33.
Ohashi K, Sequist LV, Arcila ME, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A. 2012;109:E2127–33.
Engelman JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695–706.
Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011;71:6051–60.
Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169–80.
Zakowski MF, Ladanyi KMG. EGFR mutations in small-cell lung cancers in patients who have never smoked. N Engl J Med. 2006;355:213–5.
Gong Y, Yao E, Shen R, et al. High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS One. 2009;4, e7273.
Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80.
Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–7.
Chaft JE, Oxnard GR, Sima CS, Miller VA, Riely GJ. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: Implications for clinical trial design. Clin Cancer Res. 2011;17:6298–303.
Pop O, Pirvu A, Toffart AC, Moro-Sibilot D. Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol. 2012;7:e1–2.
Overman MJ, Modak J, Kopetz S, et al. Use of research biopsies in clinical trials: Are risks and benefits adequately discussed? J Clin Oncol. 2013;31:17–22.
Peppercorn J. Toward improved understanding of the ethical and clinical issues surrounding mandatory research biopsies. J Clin Oncol. 2013;31:1–2.
Kuang Y, Rogers A, Yeap BY, et al. Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin Cancer Res. 2009;15:2630–6.
Hohenberger P, Ronellenfitsch U, Oladeji O, et al. Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour. Br J Surg. 2010;97:1854–9.
Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466–77.
Plaat BE, Hollema H, Molenaar WM, et al. Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol. 2000;18:3211–20.
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.
Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther. 2000;295:139–45.
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–32.
Heinrich MC, Wait CL, Yee KWH, Griffith DJ. STI571 inhibits the kinase activity of wild type and juxtamembrane c-kit mutants but not the exon 17 D816V mutation associated with mastocytosis. Blood. 2000;96:173b.
Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene. 2001;20:5054–8.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052–6.
van Oosterom AT, Judson IR, Verweij J, et al. Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2002;38 Suppl 5:S83–7.
Van den Abbeele AD, Badawi RD. Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer. 2002;38 Suppl 5:S60–5.
Bauer S, Yu LK, Demetri GD, Fletcher JA. Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res. 2006;66:9153–961.
Gordon PM, Fisher DE. Role for the proapoptotic factor BIM in mediating imatinib-induced apoptosis in a c-KIT-dependent gastrointestinal stromal tumor cell line. J Biol Chem. 2010;285:14109–14.
Liu Y, Tseng M, Perdreau SA, et al. Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Cancer Res. 2007;67:2685–92.
Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17:1094–100.
Le Cesne A, Ray-Coquard I, Bui BN, et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol. 2010;11:942–9.
Agaram NP, Besmer P, Wong GC, et al. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:170–81.
Liu Y, Perdreau SA, Chatterjee P, Wang L, Kuan SF, Duensing A. Imatinib mesylate induces quiescence in gastrointestinal stromal tumor cells through the CDH1-SKP2-p27Kip1 signaling axis. Cancer Res. 2008;68:9015–23.
Gupta A, Roy S, Lazar AJ, et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci U S A. 2010;107:14333–8.
Abhyankar SA, Nair N. Highlighting the role of FDG PET scan in early response assessment of gastrointestinal stromal tumor treated with imatinib mesylate. Clin Nucl Med. 2008;33:213–4.
Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753–9.
Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–5.
Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626–32.
Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–34.
Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42:1093–103.
Debiec-Rychter M, Wasag B, Stul M, et al. Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. J Pathol. 2004;202:430–8.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–9.
Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26:5360–7.
Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26:5352–9.
MetaGIST. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010;28:1247–53.
Janeway KA, Albritton KH, Van Den Abbeele AD, et al. Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib. Pediatr Blood Cancer. 2009;52:767–71.
Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J. Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell. 2007;130:323–34.
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11:865–78.
Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357–564.
Weisberg E, Wright RD, Jiang J, et al. Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Gastroenterology. 2006;131:1734–42.
Gajiwala KS, Wu JC, Christensen J, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci U S A. 2009;106:1542–7.
Biron P, Cassier PA, Fumagalli E, et al. Grp ESTBS. Outcome of patients (pts) with PDGFRA(D842V) mutant gastrointestinal stromal tumor (GIST) treated with imatinib (IM) for advanced disease. J Clin Oncol. 2010;28:15s (suppl; abstr 10051)
Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005;128:270–9.
Liegl B, Kepten I, Le C, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216:64–74.
Miselli FC, Casieri P, Negri T, et al. c-Kit/PDGFRA gene status alterations possibly related to primary imatinib resistance in gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:2369–77.
Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res. 2004;10:3282–90.
Grimpen F, Yip D, McArthur G, et al. Resistance to imatinib, low-grade FDG-avidity on PET, and acquired KIT exon 17 mutation in gastrointestinal stromal tumour. Lancet Oncol. 2005;6:724–7.
Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764–74.
Wakai T, Kanda T, Hirota S, Ohashi A, Shirai Y, Hatakeyama K. Late resistance to imatinib therapy in a metastatic gastrointestinal stromal tumour is associated with a second KIT mutation. Br J Cancer. 2004;90:2059–61.
Loughrey MB, Waring PM, Dobrovic A, Demetri G, Kovalenko S, McArthur G. Polyclonal resistance in gastrointestinal stromal tumor treated with sequential kinase inhibitors. Clin Cancer Res. 2006;12(20 Pt 1):6205–6. author reply 6206-6207.
Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006;12:1743–9.
Mahadevan D, Cooke L, Riley C, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007;26:3909–19.
Takahashi T, Serada S, Ako M, et al. New findings of kinase switching in gastrointestinal stromal tumor under imatinib using phosphoproteomic analysis. Int J Cancer. 2013;133:2737–43.
Sakurama K, Noma K, Takaoka M, et al. Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor. Mol Cancer Ther. 2009;8:127–34.
Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327:293–7.
Mascaux C, Iannino CN, Martin B, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer. 2005;92:131–9.
Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008;9:962–72.
Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–5.
Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–8.
Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.
Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.
Edkins S, O’Meara S, Parker A, et al. Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol Ther. 2006;5:928–32.
Janakiraman M, Vakiani E, Zeng Z, et al. Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res. 2010;70:5901–11.
Smith G, Bounds R, Wolf H, Steele RJ, Carey FA, Wolf CR. Activating K-Ras mutations out with ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine. Br J Cancer. 2010;102:693–703.
Vaughn CP, Zobell SD, Furtado LV, Baker CL, Samowitz WS. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer. 2011;50:307–12.
Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.
Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:2240–7.
Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–75.
Rosenberg DW, Yang S, Pleau DC, et al. Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res. 2007;67:3551–4.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch repair status. Nature. 2002;418:934.
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–95.
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.
Jhawer M, Goel S, Wilson AJ, et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 2008;68:1953–61.
Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1:508–23.
Valtorta E, Misale S, Sartore-Bianchi A, et al. KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy. Int J Cancer. 2013;133:1259–65.
Mekenkamp LJ, Tol J, Dijkstra JR, et al. Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients. BMC Cancer. 2012;12:292.
Mita H, Toyota M, Aoki F, et al. A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth. BMC Cancer. 2009;9:198.
Wagner PL, Perner S, Rickman DS, et al. In situ evidence of KRAS amplification and association with increased p21 levels in non-small cell lung carcinoma. Am J Clin Pathol. 2009;132:500–5.
Sasaki H, Hikosaka Y, Kawano O, Moriyama S, Yano M, Fujii Y. Evaluation of Kras gene mutation and copy number gain in non-small cell lung cancer. J Thorac Oncol. 2011;6:15–20.
Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27:5924–30.
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.
Cremolini C, Di Bartolomeo M, Amatu A, et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 2015;26:2092–7.
Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3:99ra86.
Bardelli A, Corso S, Bertotti A, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013;3:658–73.
Samuels Y, Wang Z, Bardella A, et al. High frequency of mutations of the PIK3CA gene in human cancer. Apoptosis. 2004;9:667–76.
Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br J Cancer. 2006;94:455–9.
Goel A, Arnold CN, Niedzwiecki D, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64:3014–21.
De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemo-therapy refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62.
Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One. 2009;4, e7287.
Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532–6.
Hobor S, Van Emburgh BO, Crowley E, Misale S, Di Nicolantonio F, Bardelli A. TGF-α and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells. Clin Cancer Res. 2014;20:6429–38.
Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A. Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution Cancer Discov. 2014;4:1269–80.
Montagut C, Dalmases A, Bellosillo B, et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012;18:221–3.
Diaz Jr LA, Sausen M, Fisher GA, Velculescu VE. Insights into therapeutic resistance from whole-genome analyses of circulating tumor DNA. Oncotarget. 2013;4:1856–7.
Mohan S, Heitzer E, Ulz P, et al. Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing. PLoS Genet. 2014;10, e1004271.
Diaz LA, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537–40.
Misale S, Arena S, Lamba S, et al. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci Transl Med. 2014;6:224ra26.
Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.
Jones HE, Goddard L, Gee JM, et al. Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer. 2004;11:793–814.
Camirand A, Zakikhani M, Young F, Pollak M. Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells. Breast Cancer Res. 2005;7:R570–9.
Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoël MJ, et al. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res. 2009;15:5445–56.
Ruckhäberle E, Rody A, Engels K, et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res. Treat. 2008;112:41–52.
Sukocheva O, Wang L, Verrier E, Vadas MA, Xia P. Restoring endocrine response in breast cancer cells by inhibition of the sphingosine kinase-1 signaling pathway. Endocrinology. 2000;150:4484–92.
Rosa R, Marciano R, Malapelle U, et al. Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models. Clin Cancer Res. 2013;19:138–47.
Gao Y, Gao F, Chen K, Tian ML, Zhao DL. Sphingosine kinase 1 and resistance. Drug Des Devel Ther. 2015;9:3239–45.
Jia Y, Liu M, Huang W, et al. Recombinant human endostatin Endostar inhibits tumor growth and metastasis in a mouse xenograft model of colon cancer. Pathol Oncol Res. 2012;18:315–23.
Jitawatanarat P, Wee W. Update on antiangiogenic therapy in colorectal cancer: aflibercept and regorafenib. J Gastrointest Oncol. 2013;4:231–8.
Edelman MJ, Mao L. Resistance to anti-angiogenic agents: a brief review of mechanisms and consequences. Transl Lung Cancer Res. 2013;2:304–7.
Prager GW, Poettler M, Unseld M, Zielinski CC. Angiogenesis in cancer: Anti-VEGF escape mechanisms. Transl Lung Cancer Res. 2012;1:14–25.
Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor. Oncologist. 2015;20:660–73.
Shi YH, Bingle L, Gong LH, Wang YX, Corke KP, Fang WG. Basic FGF augments hypoxia-induced HIF-1-alpha expression and VEGF release in T47D breast cancer cells. Pathology. 2007;39:396–400.
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.
Ayers M, Awad M, Malone D, et al. Association of K-ras status with efficacy end points from a phase 1/2 study of brivanib in combination with cetuximab in patients with advanced or metastatic colorectal cancer (CRC). American Society of Clinical Oncology Gastrointestinal Cancers (ASCO-GI) Symposium, San Francisco, 2009; Abstract no. 375.
Garrett CR, Siu LL, El-Khoueiry A, et al. Phase I dose escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br J Cancer. 2011;105:44–52.
Clinicaltrials.gov. Cetuximab with or without brivanib in treating patients with metastatic colorectal cancer. http://clinicaltrials.gov/ct2/. Accessed 30 Nov 2010.
Shojaei F, Wu X, Malik AK, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+ Gr1+ myeloid cells. Nat Biotechnol. 2007;25:911–20.
Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315:971–9.
Faivre S, Demetri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov. 2007;6:734–45.
Shojaei F, Wu X, Qu X, et al. GCSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A. 2009;106:6742–7.
Mirone G, Perna S, Shukla A, Marfe G. Involvement of Notch-1 in resistance to regorafenib in colon cancer cells. J Cell Physiol. 2015;231:1097–105.
Huang D, Ding Y, Li Y, et al. Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma. Cancer Res. 2010;70:1053–62.
Adelaiye R, Ciamporcero E, Miles KM, et al. Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications. Mol Cancer Ther. 2015;14:513–22.
Gotink KJ, Verheul HMW. Anti-angiogenic tyrosine kinase inhibitors what is their mechanism of action? Angiogenesis. 2010;13:1–14.
Hammers HJ, Verheul HM, Salumbides B, et al. Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study. Mol Cancer Ther. 2010;9:1525–35.
Behnsawy HM, Shigemura K, Meligy FY, et al. Possible role of sonic hedgehog and epithelial-mesenchymal transition in renal cell cancer progression. Korean J Urol. 2013;54:547–54.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.
Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.
Cecconi O, Calorini L, Mannini A, Mugnai G, Ruggieri S. Enhancement of lungcolonizing potential of murine tumor cell lines co-cultivated with activated macrophages. Clin Exp Metastasis. 1997;15:94–101.
Oosterling SJ, van der Bij GJ, Meijer GA, et al. Macrophages direct tumour histology and clinical outcome in a colon cancer model. J Pathol. 2005;207:147–55.
Miselis NR, Wu ZJ, Van Rooijen N, Kane AB. Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma. Mol Cancer Ther. 2008;7:788–99.
Chen JJ, Yao PL, Yuan A, et al. Upregulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin Cancer Res. 2003;9:729–37.
Sundar SS, Ganesan TS. Role of lymphangiogenesis in cancer. J Clin Oncol. 2007;25:4298–307.
Dannenmann SR, Thielicke J, Stöckli M, et al. Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma. Oncoimmunology. 2013;2, e23562.
Huang D, Ding Y, Zhou M, et al. Interleukin-8 mediates resistance to antiangiogenic agent. Cancer Res. 2010;70:1063–71.
Bielecka ZF, Czarnecka AM, Solarek W, Kornakiewicz A, Szczylik C. Mammalian target of rapamycin inhibitors resistance mechanisms in clear cell renal cell carcinoma. Curr Signal Transduct Ther. 2014;8:218–28.
Armulik A, Genové G, Betsholtz C. Pericytes developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21:193–215.
Hall AP. Review of the pericyte during angiogenesis and its role in cancer and diabetic retinopathy. Toxicol Pathol. 2006;34:763–75.
Cao Z, Shang B, Zhang G, et al. Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis. Biochim Biophys Acta. 1836;2013:273–86.
Gotink KJ, Broxterman HJ, Labots M, et al. Lysosomal sequestration of sunitinib a novel mechanism of drug resistance. Clin Cancer Res. 2011;17:7337–46.
Kassouf W, Dinney CP, Brown G, et al. Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of Gefitinib in bladder cancer cells. Cancer Res. 2005;65:10524–35.
Shrader M, Pino MS, Brown G, et al. Molecular correlates of gefitinib responsiveness in human bladder cancer cells. Mol Cancer Ther. 2007;6:277–85.
Black PC, Brown GA, Inamoto T, et al. Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells. Clin Cancer Res. 2008;14:1478–86.
Li J, Lin B, Li X, Tang X, He Z, Zhou K. Biomarkers for predicting response to tyrosine kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells. Oncol Rep. 2015;33:951–7.
Knievel J, Schulz WA, Greife A, et al. Multiple mechanisms mediate resistance to sorafenib in urothelial cancer. Int J Mol Sci. 2014;15:20500–17.
Cox AD, Der CJ. The RAF inhibitor paradox: unexpected consequences of targeted drugs. Cancer Cell. 2010;17:221–3.
Pinto-Leite R, Carreira I, Melo J, et al. Genomic characterization of three urinary bladder cancer cell lines: understanding genomic types of urinary bladder cancer. Tumour Biol. 2014;35:4599–617.
Rose A, Grandoch M, vom Dorp F, et al. Stimulatory effects of the multi-kinase inhibitor sorafenib on human bladder cancer cells. Br J Pharmacol. 2010;160:1690–8.
Sturm OE, Orton R, Grindlay J, et al. The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Sci Signal. 2010;3:ra90.
Nawroth R, Stellwagen F, Schulz WA, et al. S6K1 and 4E-BP1 are independent regulated and control cellular growth in bladder cancer. PLoS One. 2011;6, e27509.
Ewald F, Ueffing N, Brockmann L, et al. The role of c-FLIP splice variants in urothelial tumours. Cell Death Dis. 2011;2, e245.
Di Lorenzo G, Tortora G, D’Armiento FP, et al. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res. 2002;8:3438–44.
Traish AM, Morgentaler A. Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth. Br J Cancer. 2009;101:1949–56.
Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.
Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J. The transcriptional response to Raf activation is almost completely dependent on Mitogen-activated Protein Kinase Kinase activity and shows a major autocrine component. Mol Biol Cell. 2005;15:3450–63.
Festuccia C, Gravina GL, Millimaggi D, et al. Uncoupling of the epidermal growth factor receptor from downstream signal transduction molecules guides the acquired resistance to gefitinib in prostate cancer cells. Oncol Rep. 2007;18:503–11.
Culig Z, Bartsch G, Hobisch A. Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth. Mol Cell Endocrinol. 2002;197:231–8.
Chen T, Wang LH, Farrar WL. Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Cancer Res. 2000;60:2132–5.
Michalaki V, Syrigos K, Charles P, Waxman J. Serum levels of IL-6 and TNF-alpha correlate with clinicopathological features and patient survival in patients with prostate cancer. Br J Cancer. 2004;90:2312–6.
Kutikov A, Makhov P, Golovine K, et al. Interleukin-6: a potential biomarker of resistance to multitargeted receptor tyrosin kinase inhibitors in castration-resistant prostate cancer. Urology. 2011;78:968.e7–11.
Siu MK, Abou-Kheir W, Yin JJ, et al. Loss of EGFR signaling regulated miR-203 promotes prostate cancer bon metastasis and tyrosine kinase inhibitors resistance. Oncotarget. 2014;5:3770–84.
Antonarakis ES, Carducci MA. Targeting angiogenesis for the treatment of prostate cancer. Expert Opin Ther Targets. 2012;16:365–76.
Blanc J, Geney R, Menet C. Type II kinase inhibitors: an opportunity in cancer for rational design. Anticancer Agents Med Chem. 2013;13:731–47.
Bussolati B, Grange C, Camussi G. Tumor exploits alternative strategies to achieve vascularization. FASEB J. 2001;25:2874–82.
Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St Croix B. Genes that distinguish physiological and pathological angiogenesis. Cancer Cell. 2007;11:539–54.
Hida K, Hida Y, Amin DN, et al. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res. 2004;64:8249–55.
Bussolati B, Deambrosis I, Russo S, Deregibus MC, Camussi G. Altered angiogenesis and survival in human tumor-derived endothelial cells. FASEB J. 2003;17:1159–61.
Xiong YQ, Sun HC, Zhang W, et al. Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells. Clin Cancer Res. 2009;15:4838–46.
Fiorio Pla A, Brossa A, Bernardini M, et al. Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib. BMC Cancer. 2014;14:939.
Sahin O, Wang Q, Brady SW, et al. Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors. Cell Res. 2014;24:542–59.
Tinoco G, Warsch S, Glück S, Avancha K, Montero AJ. Treating breast cancer in the 21st century: emerging biological therapies. J Cancer. 2013;4:117–32.
Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol. 2007;18:977–84.
Hudis CA. Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39–51.
Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012;9:16–32.
Reynolds K, Sarangi S, Bardia A, Dizon DS. Precision medicine and personalized breast cancer: combination pertuzumab therapy. Pharmgenomics Pers Med. 2014;7:95–105.
Pallis AG, Syrigos KN. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC. Lung Cancer. 2013;80:120–30.
Moore MJ, Goldstein D, Hamm J, National Cancer Institute of Canada Clinical Trials Group, et al. Erlotinib Plus Gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials. Group J Clin Oncol. 2007;25:1960–6.
Wilson TR, Fridlyand J, Yan Y, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487:505–9.
Gallardo A, Lerma E, Escuin D, et al. Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer. 2012;106:1367–73.
Wang L, Zhang Q, Zhang J, et al. PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer. 2011;11:248.
Diermeier S, Horváth G, Knuechel-Clarke R, Hofstaedter F, Söllosi J, Brockhoff G. Epidermal growth factor receptor coexpression modulates susceptibility to herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation. Exp Cell Res. 2005;304:604–19.
Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, Minami H. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol. 2010;21:255–62.
Figueroa-Magalhães MC, Jelovac D, Connolly RM, Wolff AC. Treatment of HER2-positive breast cancer. Breast. 2014;23:128–36.
D'Alessio A, De Luca A, Maiello MR, et al. Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells. Breast Cancer Res Treat. 2009;123:387–96.
Versola MB, Burris S, Jones H, et al. Clinical activity of GW572016 in EGF10003 in patients with solid tumors. J Clin Oncol. 2004;22 (14S July 15 Suppl):3047.
Gomez HL, Doval DC, Chavez MA, et al. Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol. 2008;26:2999–3005.
Press MF, Finn RS, Cameron D, et al. HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res. 2008;14:7861–70.
Ryan QA, Ibrahim MH, Cohen J, et al. FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist. 2008;13:1114–9.
Zhou X, Cella D, Cameron D, et al. Lapatinib plus capecitabine versus capecitabine alone for HER2+ (ErbB2+) metastatic breast cancer: quality-of-life assessment. Breast Cancer Res Treat. 2009;117:577–89.
Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803–14.
Toi M, Iwata M, Fujiwara Y, et al. Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies. Br J Cancer. 2009;101:1676–82.
Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, Spector NL. Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and 73 ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene. 2005;24:6213–21.
Vazquez-Martin A, Oliveras-Ferraros C, del Barco S, Martín-Castillo B, Menéndez JA. mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb). Clin Transl Oncol. 2009;11:455–9.
Xia W, Bacus S, Hegde P, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A. 2006;103:7795–800.
Tam IY, Leung EL, Tin VP, et al. Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations. Mol Cancer Ther. 2009;8:2142–51.
Bhosle J, Kiakos K, Porter AC, et al. Treatment with gefitinib or lapatinib induces drug resistance through downregulation of topoisomerase IIα expression. Mol Cancer Ther. 2013;12:2897–908.
Nevo J, Mattila E, Pellinen T, et al. Mammary-derived growth inhibitor alters traffic of EGFR and induces a novel form of cetuximab resistance. Clin Cancer Res. 2009;15:6570–81.
Meng X, Li Y, Tang H, et al. Drug response to HER2 gatekeeper T798M mutation in HER2-positive breast cancer. Amino Acids. 2015;48:487–97.
Vecchione A, Belletti B, Lovat F, et al. A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis. Proc Natl Acad Sci U S A. 2013;110:9845–50.
Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302–8.
Bast Jr RC, Hennessy B, Mills GB. The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer. 2009;9:415–28.
Verhaak RG, Tamayo P, Yang JY, et al. Cancer genome atlas research network prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 2013;123:517–25.
Cho KR, Shih IM. Ovarian cancer. Annu Rev Pathol. 2009;4:287–313.
Cancer Genome Atlas Research, Networks. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.
Cancer Genome Atlas Research, Networks, Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.
Cuatrecasas M, Villanueva A, Matias-Guiu X, Prat J. K-ras mutations in mucinous ovarian tumors – a clinicopathologic and molecular study of 95 cases. Cancer. 1997;79:1581–6.
Bookman MA. Biological therapy of ovarian cancer: current directions. Semin Oncol. 1998;25:381–96.
Kaye SB, Poole CJ, Dańska-Bidzińska A, et al. A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin based chemotherapy in patients with relapsed platinum sensitive ovarian cancer. Ann Oncol. 2013;24:145–52.
Amler L, Makhija S, Januario T, et al. Her 2 pathway gene expression analysis in a phase II study of pertuzumab + gemcitabine vs. gemcitabine + placebo in patients with platinum resistant epithelial ovarian cancer. J Clin Oncol. 2008;26:abstract 5562.
Makhija S, Glenn D, Ueland F, et al. Results from a phase II randomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer. J Clin Oncol. 2007;25:18S-abstract 5507.
Gordon MS, Matei D, Aghajanian C, et al. Clinical activity of pertuzumab (rhuMAb2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predicative relationship between tumor HER 2 activation status. J Clin Oncol. 2006;24:4324–32.
Schilder RJ, Sill MW, Chen X, et al. Phase II study of Getinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecological Oncology Group Study. Clinical Cancer Res. 2005;11:5539–48.
Nimeiri HS, Oza AM, Morgan RJ, et al. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 2008;110:49–55.
Apte SM, Bucana CD, Killion JJ, Gershenson DM, Fidler IJ. Expression of platelet-derived growth factor and activated receptor in clinical specimens of epithelial ovarian cancer and ovarian carcinoma cell lines. Gynecol Oncol. 2004;93:78–86.
Della Pepa C, Tonini G, Pisano C, et al. Ovarian cancer standard of care: are there real alternatives? Chin J Cancer. 2015;34:17–27.
Berasain C. Hepatocellular carcinoma and sorafenib: too many resistance mechanisms? Gut. 2013;62:1674–5.
Tang TC, Man S, Xu P, et al. Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia. 2010;12:928–40.
Kuczynski EA, Lee CR, Man S, Chen E, Kerbel RS. Effects of sorafenib dose on acquired reversible resistance and toxicity in hepatocellular carcinoma. Cancer Res. 2015;75:2510–9.
Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–9.
Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170:1445–53.
Humphrey PA, Gangarosa LM, Wong AJ, et al. Deletion-mutant epidermal growth factor 76 receptor in human gliomas: effects of type II mutation on receptor function. Bioch and Biop Res Comm. 1991;178:1413–20.
Lee JC, Vivanco I, Beroukhim R, et al. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med. 2006;3, e485.
Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60:1383–7.
Peschard P, Park M. From Tpr-Met to Met, tumorigenesis and tubes. Oncogene. 2007;26:1276–85.
Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995;55:5536–9.
Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes and Dev. 2007;21:2683–710.
Downward J, Parker P, Waterfield MD. Autophosphorylation sites on the epidermal growth factor receptor. Nature. 1984;311:483–5.
Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19:6550–65.
Choe G, Horvath S, Cloughesy TF, et al. Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res. 2003;63:2742–6.
Tanaka K, Babic I, Nathanson D, et al. Oncogenic EGFR signaling activates an mTORC2-NF-kappaB pathway that promotes chemotherapy resistance. Cancer Discov. 2011;1:524–38.
Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012–24.
Wang SI, Puc J, Li J, et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 1997;57:4183–6.
Bonavia R, Inda MM, Vandenberg S, et al. EGFRvIII promotes glioma angiogenesis and growth through the NF-kappaB, interleukin-8 pathway. Oncogene. 2012;31:4054–66.
Wu JL, Abe T, Inoue R, Fujiki M, Kobayashi H. IkappaBalphaM suppresses angiogenesis and tumorigenesis promoted by a constitutively active mutant EGFR in human glioma cells. Neurol Res. 2004;26:785–91.
Wang SC, Hung MC. Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clin Cancer Res. 2009;15:6484–9.
Boerner JL, Demory ML, Silva C, Parsons SJ. Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Mol Cell Biol. 2004;24:7059–71.
Snuderl M, Fazlollahi L, Le LP, et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell. 2011;20:810–7.
Little SE, Popov S, Jury A, et al. Receptor tyrosine kinase genes amplified in glioblastoma exhibit a mutual exclusivity in variable proportions reflective of individual tumor heterogeneity. Cancer Res. 2012;72:1614–20.
Jun HJ, Acquaviva J, Chi D, J et al. Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme. Oncogene. 2012;31:3039–50.
Bao SQ, Wu Q, McLendon RE, et al. Glioma stem cells promote radio resistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.
Tamura K, Aoyagi M, Ando N, et al. Expansion of CD133-positive glioma cells in recurrent de novo glioblastomas after radiotherapy and chemotherapy. J Neuros. 2013;119:1145–55.
Eimer S, Dugay F, Airiau K, et al. Cyclopamine cooperates with EGFR inhibition to deplete stem-like cancer cells in glioblastoma-derived spheroid cultures. Neuro Oncol. 2012;14:1441–51.
Wykosky J, Hu J, Gomez GG, et al. A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma. Cancer Res. 2015;15(75):394–404.
Aljohani H, Koncar RF, Zarzour A, Park BS, Lee SH, Bahassi el M. ROS1 amplification mediates resistance to gefitinib in glioblastoma cells Oncotarget. 2015;6:20388–95.
Roth P, Weller M. Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro Oncol. 2014;16:viii14-19.
Kang CS, Pu PY, Li YH, et al. An in vitro study on the suppressive effect of glioma cell growth induced by plasmid-based small interference RNA (siRNA) targeting human epidermal growth factor receptor. J Neurooncol. 2005;74:267–73.
Nagane M, Levitzki A, Gazit A, Huang HJ. Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sci U S A. 1998;95:5724–9.
Fan QW, Cheng CK, Gustafson WC, et al. EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell. 2013;24:438–49.
Inda MM, Bonavia R, Mukasa A, et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev. 2010;24:1731–45.
Johnson H, Del Rosario AM, Bryson BD, Schroeder MA, Sarkaria JN, White FM. Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts. Mol Cell Proteomics. 2012;11:1724–40.
Lal B, Goodwin CR, Sang Y, et al. EGFRvIII and c-Met pathway inhibitors synergize against PTEN-null/EGFRvIII+ glioblastoma xenografts. Mol Cancer Ther. 2009;8:1751–60.
Hu J, Jo M, Cavenee WK, Furnari F, VandenBerg SR, Gonias SL. Crosstalk between the urokinase-type plasminogen activator receptor and EGF receptor variant III supports survival and growth of glioblastoma cells. Proc Natl Acad Sci U S A. 2011;108:15984–9.
Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti–epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 2002;62:200–7.
Lotsch D, Steiner E, Holzmann K, et al. Major vault protein supports glioblastoma survival and migration by upregulating the EGFR/PI3K signalling axis. Oncotarget. 2013;4:1904–18.
Wick W, Weller M, van den Bent M, Stupp R. Bevacizumab and recurrent malignant gliomas: a European perspective. J Clin Oncol. 2010;28:e188–9; author reply e190–182.
Zhang M, Ye G, Li J, Wang Y. Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy. Brain Tumor Pathol. 2015;32:229–36.
Zuniga RM, Torcuator R, Jain R, et al. Efficacy, safety and patterns of response and recurrence in patients with recurrent high‐grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol. 2009;91:329–36.
Bergers G, Hanahan D. Modes of resistance to anti‐angiogenic therapy. Nat Rev Cancer. 2008;8:592–603.
Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010;120:694–705.
Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A. 2007;104:17069–74.
Reardon DA, Turner S, Peters KB, et al. A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw. 2011;9:414–27.
Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.
Kunkel P, Ulbricht U, Bohlen P, et al. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor- 2. Cancer Res. 2001;61:6624–8.
Kamoun WS, Ley CD, Farrar CT, et al. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol. 2009;27:2542–52.
Ciardiello F, Bianco R, Damiano V, et al. Antiangiogenic and antitumor activity of anti–epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res. 2000;6:3739–47.
Ko AH, Youssoufian H, Gurtler J, et al. A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Invest New Drugs. 2012;30:1597–606.
Heinemann V, Vehling-Kaiser U, Waldschmidt D, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013;62:571–9.
Philip PA, Lutz MP. Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer. Pancreas. 2015;44:1046–52.
Kim ST, Lim do H, Jang KT. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011;10:1993–9.
Propper D, Davidenko I, Bridgewater J, et al. Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma. Ann Oncol. 2014;25:1384–90.
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78.
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27.
Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25:2171–7.
Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinumrefractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5568–77.
Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5578–87.
Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62:7350–6.
Bentzen SM, Atasoy BM, Daley FM, et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol. 2005;23:5560–7.
Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol. 2011;12:333–43.
Wirth LJ, Allen AM, Posner MR, et al. Phase I dose-finding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck. Ann Oncol. 2010;21:342–7.
Ramakrishnan MS, Eswaraiah A, Crombet T, et al. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. MAbs. 2009;1:41–8.
Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22:77–85.
Martins RG, Parvathaneni U, Bauman JE, et al. Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. J Clin Oncol. 2013;31:1415–21.
Harrington K, Berrier A, Robinson M, et al. Randomised Phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease. Eur J Cancer. 2013;49:1609–18.
Del Campo JM, Hitt R, Sebastian P, et al. Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck. Br J Cancer. 2011;105:618–27.
de Souza JA, Davis DW, Zhang Y, et al. A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012;18:2336–43.
Seiwert TY, Fayette J, Cupissol D, et al. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol. 2014;25:1813–20.
Carla C, Daris F, Cecilia B, Francesca B, Francesca C, Paolo F. Angiogenesis in head and neck cancer: a review of the literature. J Oncol. 2012;2012:358472.
Hasina R, Whipple M, Martin L, Kuo WP, Ohno-Machado L, Lingen MW. Angiogenic heterogeneity in head and neck squamous cell carcinoma: biological and therapeutic implications Lab. Invest. 2008;88:342–53.
Vokes EE, Cohen EEW, Mauer AM, et al. A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck (HNC). J Clin Oncol. 2005;23:(16 Suppl):5504.
Karamouzis MV, Friedland D, Johnson R, Rajasenan K, Branstetter B, Argiris A. Phase II trial of pemetrexed (P) and bevacizumab (B) in patients (pts) withrecurrent or metastatic head and neck squamous cell carcinoma (HNSCC): an interiman analysis. J Clin Oncol. 2007;25(18 Suppl):6049.
Choong NW, Kozloff M, Taber D, et al. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Invest New Drugs. 2010;28:677–83.
Fountzilas G, Fragkoulidi A, Kalogera-Fountzila A, et al. A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer. Cancer Chemoth Pharmacol. 2010;65:649–60.
Machiels JP, Henry S, Zanetta S, et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol. 2010;28:21–8.
Kim S, Yazici YD, Calzada G, et al. Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther. 2007;6:1785–92.
Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25:3766–73.
Williamson SK, Moon J, Huang CH, et al. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: southwest Oncology Group Study S0420. J Clin Oncol. 2010;28:3330–5.
Conflict of Interest Statement
All authors have no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Mirone, G., Perna, S., Marfe, G. (2016). Resistance to Tyrosine Kinase Inhibitors in Different Types of Solid Cancer. In: Focosi, D. (eds) Resistance to Tyrosine Kinase Inhibitors. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-46091-8_2
Download citation
DOI: https://doi.org/10.1007/978-3-319-46091-8_2
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-46090-1
Online ISBN: 978-3-319-46091-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)