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Functional Consequences and Clinical Significance of Tyrosine Kinase Inhibitors in Advanced Colorectal Cancer

  • Mamoon Ur Rashid
  • Ishtiaq Hussain
  • Sundas Jehanzeb
  • Saeed Ali
  • Akriti Gupta Jain
  • Ranjeet Kumar
  • Neelam Khetpal
  • Sarfraz AhmadEmail author
Chapter

Abstract

Colorectal cancer (CRC) is an important public health issue as the 5-year prognosis is <20% for newly diagnosed metastatic CRC (mCRC). In recent years, screening modalities have led to early detection of the disease, which has shown some promise for improved survival. The advancements in adjunctive treatments and aggressive surgical treatment are also partly responsible for this success, but the deeper understanding of carcinogenesis and targeted molecular therapy has made a stronger impact with the emergence of newer targets in the recent past. Particularly, the development and FDA approval of newer drugs, including capecitabine, irinotecan, oxaliplatin, monoclonal antibodies that block either VEGF (bevacizumab, aflibercept, and ramucirumab) or the EGFR (cetuximab and panitumumab), and most recently, trifluridine/tipiracil and regorafenib (TAS-102), have been remarkable in this area of research. The clinical benefits of these drugs are now generally acceptable/established for mCRC patients, with the median overall survival of >30 months. Currently, limitation in the effectiveness of tyrosine kinase inhibitors (TKIs) is due to (i) combination chemotherapy use that necessitates lowering of the dose density for toxicity profile management, and (ii) these drugs have mainly been developed in molecularly unselected population. The main challenge now is the identification of more reliable and 116 specific predictive biomarkers for selecting the most suitable therapy for mCRC. So far, the only well-established/reliable biomarker for mCRC treatment is RAS mutational status, which predicts negative response to anti-EGFR therapy. Current recommendation for the BRAF mutational status has also been given by the NCCN and the ESMO. Unlike VEGF inhibitor therapy, the resistance mechanisms in the EGFR inhibitor therapy are well understood, as are the drugs blocking the downstream RAS-MAPK pathway. Notably, a number of clinical trials on targeting the RAS signaling pathway have revealed promising efficacy in chemo-refractory mCRC. This chapter discusses the role of TKIs in advanced CRC from both translational and clinical research points of view.

Keywords

Colorectal cancer Tyrosine kinase inhibitors EGFR VEGF 

Notes

Conflict of Interest

None of the authors has any potential financial or commercial conflict of interest associated with this research manuscript (chapter).

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA: Cancer J Clin 61(2):69–90Google Scholar
  2. 2.
    Pino MS, Chung DC (2010) The chromosomal instability pathway in colon cancer. Gastroenterology 138(6):2059–2072CrossRefGoogle Scholar
  3. 3.
    Armaghany T, Wilson JD, Chu Q, Mills G (2012) Genetic alterations in colorectal cancer. Gastrointest Cancer Res GCR 5(1):19PubMedGoogle Scholar
  4. 4.
    Sieber OM, Heinimann K, Tomlinson IP (2003) Genomic instability—the engine of tumorigenesis? Nat Rev Cancer 3(9):701CrossRefGoogle Scholar
  5. 5.
    Shih I-M, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B (2001) Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res 61(3):818–822PubMedGoogle Scholar
  6. 6.
    Michor F, Iwasa Y, Vogelstein B, Lengauer C, Nowak MA (2005) Can chromosomal instability initiate tumorigenesis? Semin Cancer Viol 2005: ElsevierGoogle Scholar
  7. 7.
    Cottrell S, Bodmer W, Bicknell D, Kaklamanis L (1992) Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet 340(8820):626–630CrossRefGoogle Scholar
  8. 8.
    Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN et al (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359(6392):235CrossRefGoogle Scholar
  9. 9.
    Filippo CD, Luceri C, Caderni G, Pacini M, Messerini L, Biggeri A et al (2002) Mutations of the APC gene in human sporadic colorectal cancers. Scand J Gstroenterol 37(9):1048–1053CrossRefGoogle Scholar
  10. 10.
    Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170CrossRefGoogle Scholar
  11. 11.
    Polakis P (1997) The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta (BBA)-Rev Cancer 1332(3):F127–FF47CrossRefGoogle Scholar
  12. 12.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532CrossRefGoogle Scholar
  13. 13.
    Lane D, Benchimol S (1990) p53: oncogene or anti-oncogene. Genes Dev 4(1):1–8CrossRefGoogle Scholar
  14. 14.
    Adrover E, Maestro M, Sanz-Casla M, Del Barco V, Cerdán J, Fernández C et al (1999) Expression of high p53 levels in colorectal cancer: a favourable prognostic factor. Br J Cancer 81(1):122CrossRefGoogle Scholar
  15. 15.
    Popat S, Chen Z, Zhao D, Pan H, Hearle N, Chandler I et al (2006) A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer. Ann Oncol 17(12):1810–1817CrossRefGoogle Scholar
  16. 16.
    Forcet C, Ye X, Granger L, Corset V, Shin H, Bredesen DE et al (2001) The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. Proc Natl Acad Sci U S A 98(6):3416–3421CrossRefGoogle Scholar
  17. 17.
    Ogino S, Nosho K, Irahara N, Shima K, Baba Y, Kirkner GJ et al (2009) Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers. J Clin Oncol 27(27):4591CrossRefGoogle Scholar
  18. 18.
    Watanabe T, Wu T-T, Catalano PJ, Ueki T, Satriano R, Haller DG et al (2001) Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344(16):1196–1206CrossRefGoogle Scholar
  19. 19.
    Geiersbach KB, Samowitz WS (2011) Microsatellite instability and colorectal cancer. Arch Pathol Lab Med 135(10):1269–1277CrossRefGoogle Scholar
  20. 20.
    Jung B, Doctolero RT, Tajima A, Nguyen AK, Keku T, Sandler RS et al (2004) Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers. Gastroenterology 126(3):64–659CrossRefGoogle Scholar
  21. 21.
    Grady WM, Carethers JM (2008) Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135(4):1079–1099CrossRefGoogle Scholar
  22. 22.
    Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR et al (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28(20):3219CrossRefGoogle Scholar
  23. 23.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934CrossRefGoogle Scholar
  24. 24.
    Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61(2):203–212CrossRefGoogle Scholar
  25. 25.
    Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127CrossRefGoogle Scholar
  26. 26.
    Sforza V, Martinelli E, Ciardiello F, Gambardella V, Napolitano S, Martini G et al (2016) Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer. World J Gastroenterol 22(28):6345CrossRefGoogle Scholar
  27. 27.
    Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y et al (2007) Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A 104(47):18654–18659CrossRefGoogle Scholar
  28. 28.
    Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345CrossRefGoogle Scholar
  29. 29.
    Lievre A, Bachet J-B, Boige V, Cayre A, Le Corre D, Buc E et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26(3):374–379CrossRefGoogle Scholar
  30. 30.
    Carracedo A, Pandolfi P (2008) The PTEN–PI3K pathway: of feedbacks and cross-talks. Oncogene 27(41):5527CrossRefGoogle Scholar
  31. 31.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554CrossRefGoogle Scholar
  32. 32.
    Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S et al (2009) PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 27(9):1477CrossRefGoogle Scholar
  33. 33.
    Yin Y, Shen W (2008) PTEN: a new guardian of the genome. Oncogene 27(41):5443CrossRefGoogle Scholar
  34. 34.
    Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J et al (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268(5215):1336–1338CrossRefGoogle Scholar
  35. 35.
    Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442CrossRefGoogle Scholar
  36. 36.
    Liu X-Q, Rajput A, Geng L, Ongchin M, Chaudhuri A, Wang J (2011) Restoration of transforming growth factor-β receptor II expression in colon cancer cells with microsatellite instability increases metastatic potential in vivo. J Biol Chem 286(18):16082–16090CrossRefGoogle Scholar
  37. 37.
    Pino MS, Kikuchi H, Zeng M, Herraiz MT, Sperduti I, Berger D et al (2010) Epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 138(4):1406–1417CrossRefGoogle Scholar
  38. 38.
    Van Cutsem E, Cervantes A, Nordlinger B, Arnold D (2014) Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(suppl_3):iii1–iii9CrossRefGoogle Scholar
  39. 39.
    Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG et al (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360(6):563–572CrossRefGoogle Scholar
  40. 40.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186CrossRefGoogle Scholar
  41. 41.
    Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358(11):1160–1174CrossRefGoogle Scholar
  42. 42.
    Martinelli E, De Palma R, Orditura M, De Vita F, Ciardiello F (2009) Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol 158(1):1–9CrossRefGoogle Scholar
  43. 43.
    Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P et al (2014) Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 15(6):569–579CrossRefGoogle Scholar
  44. 44.
    Troiani T, Martinelli E, Napolitano S, Morgillo F, Belli G, Cioffi L et al (2014) Molecular aspects of resistance to biological and non-biological drugs and strategies to overcome resistance in colorectal cancer. Curr Med Chem 21(14):1639–1653CrossRefGoogle Scholar
  45. 45.
    Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A (2014) Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov 4(11):1269–1280CrossRefGoogle Scholar
  46. 46.
    Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S et al (2013) Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 31(30):3764–3775CrossRefGoogle Scholar
  47. 47.
    Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M et al (2012) Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 48(10):1466–1475CrossRefGoogle Scholar
  48. 48.
    Douillard J-Y, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28(31):4697–4705CrossRefGoogle Scholar
  49. 49.
    Schwartzberg L, Rivera F, Karthaus M, Fasola G, Canon J-L, Yu H, et al (2013) PEAK (study 20070509): a randomized Phase 2 study of mFOLFOX6 with either panitumumab or bevacizumab as 1st-line treatment in patients with unresectable wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Gastrointestinal Cancers Symposium in San Francisco, CA; 2013Google Scholar
  50. 50.
    Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002: ElsevierGoogle Scholar
  51. 51.
    Leung DW, Cachianes G, Kuang W-J, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309CrossRefGoogle Scholar
  52. 52.
    Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S et al (2015) FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 16(13):1306–1315CrossRefGoogle Scholar
  53. 53.
    Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544CrossRefGoogle Scholar
  54. 54.
    Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers G-JM, Loosveld OJ et al (2015) Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 385(9980):1843–1852CrossRefGoogle Scholar
  55. 55.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G et al (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21(1):60–65CrossRefGoogle Scholar
  56. 56.
    Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA et al (2014) Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 50(2):320–331CrossRefGoogle Scholar
  57. 57.
    Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16(5):499–508CrossRefGoogle Scholar
  58. 58.
    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312CrossRefGoogle Scholar
  59. 59.
    Li J, Qin S, Xu R, Yau TC, Ma B, Pan H et al (2015) Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 16(6):619–629CrossRefGoogle Scholar
  60. 60.
    Sorich MJ, Wiese M, Rowland A, Kichenadasse G, McKinnon RA, Karapetis C (2014) Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 26(1):13–21CrossRefGoogle Scholar
  61. 61.
    De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G et al (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762CrossRefGoogle Scholar
  62. 62.
    Douillard J-Y, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M et al (2013) Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11):1023–1034CrossRefGoogle Scholar
  63. 63.
    Ziemke EK, Dosch JS, Maust JD, Shettigar A, Sen A, Welling TH et al (2016) Sensitivity of KRAS-mutant colorectal cancers to combination therapy that cotargets MEK and CDK4/6. Clin Cancer Res 22(2):405–414CrossRefGoogle Scholar
  64. 64.
    Ciombor KK, Wu C, Goldberg RM (2015) Recent therapeutic advances in the treatment of colorectal cancer. Annu Rev Med 66:83–95CrossRefGoogle Scholar
  65. 65.
    Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R et al (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62(23):6997–7000PubMedGoogle Scholar
  66. 66.
    Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D et al (2012) Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature 483(7388):100CrossRefGoogle Scholar
  67. 67.
    Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705–5712CrossRefGoogle Scholar
  68. 68.
    Yaeger R, Cercek A, O’Reilly EM, Reidy DL, Kemeny N, Wolinsky T et al (2015) Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res 21(6):1313–1320CrossRefGoogle Scholar
  69. 69.
    Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC et al (2015) Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600–mutant colorectal cancer. J Clin Oncol 33(34):4023CrossRefGoogle Scholar
  70. 70.
    Van Cutsem E, Lenz H-J, Köhne C-H, Heinemann V, Tejpar S, Melezínek I et al (2015) Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33(7):692–700CrossRefGoogle Scholar
  71. 71.
    De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar SKRAS (2011) BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12(6):594–603CrossRefGoogle Scholar
  72. 72.
    Huang C-H, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW et al (2007) Structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744CrossRefGoogle Scholar
  73. 73.
    Karakas B, Bachman K, Park B (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94(4):455CrossRefGoogle Scholar
  74. 74.
    Jhawer M, Goel S, Wilson AJ, Montagna C, Ling Y-H, Byun D-S et al (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68(6):1953–1961CrossRefGoogle Scholar
  75. 75.
    Arena S, Bellosillo B, Siravegna G, Martínez A, Cañadas I, Lazzari L et al (2015) Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin Cancer Res 21(9):2157–2166CrossRefGoogle Scholar
  76. 76.
    Liao X, Morikawa T, Lochhead P, Imamura Y, Kuchiba A, Yamauchi M et al (2012) Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin Cancer Res 18:2257:clincanres. 2410.011CrossRefGoogle Scholar
  77. 77.
    Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S et al (2013) Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 14(8):749–759CrossRefGoogle Scholar
  78. 78.
    Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M et al (2012) Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367(17):1596–1606CrossRefGoogle Scholar
  79. 79.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341CrossRefGoogle Scholar
  80. 80.
    Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C et al (2011) A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1(6):508–523CrossRefGoogle Scholar
  81. 81.
    Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J et al (2011) Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 3(99):99ra86–99ra86CrossRefGoogle Scholar
  82. 82.
    Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S et al (2013) Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23(5):603–617CrossRefGoogle Scholar
  83. 83.
    Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M et al (2012) Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 18(2):221CrossRefGoogle Scholar
  84. 84.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319CrossRefGoogle Scholar
  85. 85.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520CrossRefGoogle Scholar
  86. 86.
    Overman MJ, Kopetz S, McDermott RS, Leach J, Lonardi S, Lenz H-J et al (2016) Nivolumab±ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. Proc Am Soc Clin Oncol 34:3501–3501CrossRefGoogle Scholar
  87. 87.
    Bendell JC, Kim TW, Goh BC, Wallin J, Oh D-Y, Han S-W et al (2016) Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). Proc Am Soc Clin Oncol 34:3502–3502CrossRefGoogle Scholar
  88. 88.
    Ajani JA, D’Amico TA, Almhanna K, Bentrem DJ, Chao J, Das P et al (2016) Gastric cancer, version 3.2016, NCCN clinical practice guidelines in oncology. J Nat Comprehen Cancer Netw 14(10):1286–1312CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Mamoon Ur Rashid
    • 1
  • Ishtiaq Hussain
    • 2
  • Sundas Jehanzeb
    • 2
  • Saeed Ali
    • 1
  • Akriti Gupta Jain
    • 1
  • Ranjeet Kumar
    • 1
  • Neelam Khetpal
    • 1
  • Sarfraz Ahmad
    • 3
    • 4
    Email author
  1. 1.Department of Internal MedicineFlorida HospitalOrlandoUSA
  2. 2.Department of Internal MedicineKhyber Teaching HospitalPeshawarPakistan
  3. 3.FSU and UCF Colleges of MedicineOrlandoUSA
  4. 4.Gynecologic OncologyFlorida HospitalOrlandoUSA

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