Targeted Oncology

, Volume 3, Issue 2, pp 87–99 | Cite as

Can we predict the response to epidermal growth factor receptor targeted therapy?

  • Philipp C. Manegold
  • Georg Lurje
  • Alexandra Pohl
  • Yan Ning
  • Wu Zhang
  • Heinz-Josef Lenz
Review
  • 45 Downloads

Abstract

Epidermal growth factor receptor (EGFR) targeted therapy interferes with a molecular pathway that significantly regulates tumor growth, progression, and survival. Several clinical trials on EGFR targeted therapy revealed objective responses, and also improved survival in patients with different solid tumors. However, considerable differences in therapeutic efficacy were recognized across patient populations that might rely on specific characteristics of the individual patient, the tumor dependence on the EGFR pathway or alternative signaling pathways. Therefore, molecular markers that predict responsiveness to the specific targeted therapy are essential. Predictive markers will help to identify which individual patients might benefit the most from targeted therapy, and thus will help to increase efficacy and decrease toxicities. The occurrence of an acne-like skin rash was the first clinical surrogate marker in EGFR targeted therapy significantly associated with response rate. In gastrointestinal cancer patients promising predictive molecular markers have now been identified within the EGFR signaling pathway. K-ras mutations are associated with resistance to EGFR monoclonal antibodies (mAbs) in metastatic colorectal cancer patients. Moreover, high gene expression levels of EGFR ligands amphiregulin and epiregulin are indicative for improved progression-free survival (PFS) in response to EGFR targeted therapy. Favorable response to EGFR targeted therapy has been correlated with low gene expression levels of vascular endothelial growth factor (VEGF). Furthermore, germline polymorphisms within the genes of epidermal growth factor (EGF) and EGFR, cyclooxygenase-2 (Cox-2), cyclin D1, and FCGR2A/3A are of predictive value. However, these first encouraging findings are limited mostly due to the small patient numbers evaluated in retrospective studies. Thus, large prospective clinical trials are needed to validate these data.

Keywords

EGF EGFR Predictive markers Targeted therapy Gastrointestinal cancer 

Notes

Acknowledgement

Philipp C. Manegold is supported by grants from the Deutsche Forschungsgemeinschaft, Germany.

Conflict of interest statement

The author(s) has/have received or will receive benefits related directly or indirectly to the subject of this manuscript. Heinz-Josef Lenz works as a consultant or in an advisory role BMS, Pfizer, Merck, ImClone, Genentech, Response Genetics Stock; and receives honoraria from Pfizer, Merck, Genentech, Roche, Sanofi-Aventis; and research funding from National Cancer Institute, National Institutes of Health.

References

  1. 1.
    Wells A (1999) EGF receptor. Int J Biochem Cell Biol 31:637–643PubMedGoogle Scholar
  2. 2.
    Baselga J (2002) Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 7 Suppl 4:2–8Google Scholar
  3. 3.
    Normanno N, De Luca A, Bianco C et al (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2–16PubMedGoogle Scholar
  4. 4.
    Arteaga CL (2001) The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 19:32S–40SPubMedGoogle Scholar
  5. 5.
    Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2:127–137PubMedGoogle Scholar
  6. 6.
    Milas L, Mason KA, Ang KK (2003) Epidermal growth factor receptor and its inhibition in radiotherapy: in vivo findings. Int J Radiat Biol 79:539–545PubMedGoogle Scholar
  7. 7.
    Tortora G, Gelardi T, Ciardiello F et al (2007) The rationale for the combination of selective EGFR inhibitors with cytotoxic drugs and radiotherapy. Int J Biol Markers 22:S47–S52PubMedGoogle Scholar
  8. 8.
    Press MF, Lenz HJ (2007) EGFR, HER2 and VEGF pathways: validated targets for cancer treatment. Drugs 67:2045–2075PubMedGoogle Scholar
  9. 9.
    Saltz LB, Meropol NJ, Loehrer PJ Sr et al (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201–1208PubMedGoogle Scholar
  10. 10.
    Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345PubMedGoogle Scholar
  11. 11.
    Lenz HJ, Van Cutsem E, Khambata-Ford S et al (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914–4921PubMedGoogle Scholar
  12. 12.
    Chung KY, Shia J, Kemeny NE et al (2005) Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803–1810PubMedGoogle Scholar
  13. 13.
    Foon KA, Yang XD, Weiner LM et al (2004) Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 58:984–990PubMedGoogle Scholar
  14. 14.
    Sridhar SS, Seymour L, Shepherd FA (2003) Inhibitors of epidermal growth factor receptors: a review of clinical research with a focus on non-small cell lung cancer. Lancet Oncol 4:397–406PubMedGoogle Scholar
  15. 15.
    Wainberg ZA, Hecht JR (2007) Panitumumab in colorectal cancer. Expert Rev Anticancer Ther 7:967–973PubMedGoogle Scholar
  16. 16.
    Hecht JR, Patnaik A, Berlin J et al (2007) Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 110:980–988PubMedGoogle Scholar
  17. 17.
    Kris MG, Natale RB, Herbst RS et al (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–2158PubMedGoogle Scholar
  18. 18.
    Fukuoka M, Yano S, Giaccone G et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21:2237–2246PubMedGoogle Scholar
  19. 19.
    Giaccone G, Herbst RS, Manegold C et al (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 22:777–784PubMedGoogle Scholar
  20. 20.
    Herbst RS, Giaccone G, Schiller JH et al (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 22:785–794PubMedGoogle Scholar
  21. 21.
    Perez-Soler R, Chachoua A, Hammond LA et al (2004) Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22:3238–3247PubMedGoogle Scholar
  22. 22.
    Shepherd FA, Rodrigues PJ, Ciuleanu T et al (2005) Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353:123–132PubMedGoogle Scholar
  23. 23.
    Fuster LM, Sandler AB (2004) Select clinical trials of erlotinib (OSI-774) in non-small-cell lung cancer with emphasis on phase III outcomes. Clin Lung Cancer 6 Suppl 1:S24–S29Google Scholar
  24. 24.
    Moore MJ, Goldstein D, Hamm J et al (2007) 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 25:1960–1966PubMedGoogle Scholar
  25. 25.
    Kulke MH, Blaszkowsky LS, Ryan DP et al (2007) Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol 25:4787–4792PubMedGoogle Scholar
  26. 26.
    Harari PM, Allen GW, Bonner JA (2007) Biology of interactions: anti-epidermal growth factor receptor agents. J Clin Oncol 25:4057–4065PubMedGoogle Scholar
  27. 27.
    Woude GF, Kelloff GJ, Ruddon RW et al (2004) Reanalysis of cancer drugs: old drugs, new tricks. Clin Cancer Res 10:3897–3907PubMedGoogle Scholar
  28. 28.
    Kersting C, Packeisen J, Leidinger B et al (2006) Pitfalls in immunohistochemical assessment of EGFR expression in soft tissue sarcomas. J Clin Pathol 59:585–590PubMedGoogle Scholar
  29. 29.
    Bonner RF, Emmert-Buck M, Cole K et al (1997) Laser capture microdissection: molecular analysis of tissue. Science 278:1481–1483PubMedGoogle Scholar
  30. 30.
    Zhang W, Gordon M, Press OA et al (2006) Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab. Pharmacogenet Genomics 16:475–483PubMedCrossRefGoogle Scholar
  31. 31.
    Susman E (2004) Rash correlates with tumour response after cetuximab. Lancet Oncol 5:647PubMedGoogle Scholar
  32. 32.
    Perez-Soler R (2006) Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer 1(8 Suppl):S7–S14Google Scholar
  33. 33.
    Soulieres D, Senzer NN, Vokes EE et al (2004) 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 22:77–85PubMedGoogle Scholar
  34. 34.
    Gordon AN, Finkler N, Edwards RP et al (2005) Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer 15:785–792PubMedGoogle Scholar
  35. 35.
    Perez-Soler R (2003) Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? Oncology 17:23–28PubMedGoogle Scholar
  36. 36.
    Burtness B, Goldwasser MA, Flood W et al (2005) Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 23:8646–8654PubMedGoogle Scholar
  37. 37.
    Tejpar S, Peeters M, Humblet Y et al (2007) Phase I/II study of cetuximab dose-escalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), Pharmacodynamic (PD) and efficacy data. J Clin Oncol 25 (ASCO Meeting): Abstract 4037Google Scholar
  38. 38.
    Penault-Llorca F, Cayre A, Arnould L et al (2006) Is there an immunohistochemical technique definitively valid in epidermal growth factor receptor assessment? Oncol Rep 16:1173–1179PubMedGoogle Scholar
  39. 39.
    Moroni M, Veronese S, Benvenuti S et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti-EGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286PubMedGoogle Scholar
  40. 40.
    Cappuzzo F, Finocchiaro G, Rossi E et al (2007) EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol DOI  10.1093/annonc/mdm492
  41. 41.
    Sauer T, Guren MG, Noren T et al (2005) Demonstration of EGFR gene copy loss in colorectal carcinomas by fluorescence in situ hybridization (FISH): a surrogate marker for sensitivity to specific anti-EGFR therapy? Histopathology 47:560–564PubMedGoogle Scholar
  42. 42.
    Dziadziuszko R, Witta SE, Cappuzzo F et al (2006) Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer. Clin Cancer Res 12:3078–3084PubMedGoogle Scholar
  43. 43.
    Cappuzzo F, Hirsch FR, Rossi E et al (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643–655PubMedGoogle Scholar
  44. 44.
    Hirsch FR, Varella-Garcia M, McCoy J et al (2005) Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol 23:6838–6845PubMedGoogle Scholar
  45. 45.
    Italiano A, Follana P, Caroli FX et al (2008) Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number. Ann Surg Oncol 15:649–654PubMedGoogle Scholar
  46. 46.
    Miller VA, Kris MG, Shah N et al (2004) Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small cell lung cancer. J Clin Oncol 22:1103–1109PubMedGoogle Scholar
  47. 47.
    Janne PA, Gurubhagavatula S, Yeap BY et al (2004) Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, “Iressa”) on an expanded access study. Lung Cancer 44:221–230PubMedGoogle Scholar
  48. 48.
    Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139PubMedGoogle Scholar
  49. 49.
    Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedGoogle Scholar
  50. 50.
    Tsuchihashi Z, Khambata-Ford S, Hanna N et al (2005) Responsiveness to cetuximab without mutations in EGFR. N Engl J Med 353:208–209PubMedGoogle Scholar
  51. 51.
    Guo M, Liu S, Lu F (2006) Gefitinib-sensitizing mutations in esophageal carcinoma. N Engl J Med 354:2193–2194PubMedGoogle Scholar
  52. 52.
    Gilbert JA, Lloyd RV, Ames MM (2005) Lack of mutations in EGFR in gastroenteropancreatic neuroendocrine tumors. N Engl J Med 353:209–210PubMedGoogle Scholar
  53. 53.
    Kwak EL, Jankowski J, Thayer SP et al (2006) Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res 12:4283–4287PubMedGoogle Scholar
  54. 54.
    Ogino S, Meyerhardt JA, Cantor M et al (2005) Molecular alterations in tumors and response to combination chemotherapy with gefitinib for advanced colorectal cancer. Clin Cancer Res 11:6650–6656PubMedGoogle Scholar
  55. 55.
    Sudo T, Mimori K, Nagahara H et al (2007) Identification of EGFR mutations in esophageal cancer. Eur J Surg Oncol 33:44–48PubMedGoogle Scholar
  56. 56.
    Kimura T, Maesawa C, Ikeda K et al (2006) Mutations of the epidermal growth factor receptor gene in gastrointestinal tract tumor cell lines. Oncol Rep 15:1205–1210PubMedGoogle Scholar
  57. 57.
    Shaked Y, Bocci G, Munoz R et al (2005) Cellular and molecular surrogate markers to monitor targeted and non-targeted antiangiogenic drug activity and determine optimal biologic dose. Curr Cancer Drug Targets 5:551–559PubMedGoogle Scholar
  58. 58.
    Ebos JM, Lee CR, Christensen JG et al (2007) Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA 104:17069–17074PubMedGoogle Scholar
  59. 59.
    Hutcheson IR, Knowlden JM, Hiscox SE et al (2007) Heregulin beta1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells. Breast Cancer Res 9:R50PubMedGoogle Scholar
  60. 60.
    Khambata-Ford S, Garrett CR, Meropol NJ et al (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230–3237PubMedGoogle Scholar
  61. 61.
    Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308PubMedGoogle Scholar
  62. 62.
    Arber N, Shapira I, Ratan J et al (2000) Activation of c-K-ras mutations in human gastrointestinal tumors. Gastroenterology 118:1045–1050PubMedGoogle Scholar
  63. 63.
    Lee SH, Lee JW, Soung YH et al (2003) BRAF and KRAS mutations in stomach cancer. Oncogene 22:6942–6945PubMedGoogle Scholar
  64. 64.
    Lee KH, Lee JS, Suh C et al (1995) Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer. An analysis of 140 cases. Cancer 75:2794–2801PubMedGoogle Scholar
  65. 65.
    Casson AG, Wilson SM, McCart JA et al (1997) ras mutation and expression of the ras-regulated genes osteopontin and cathepsin L in human esophageal cancer. Int J Cancer 72:739–745PubMedGoogle Scholar
  66. 66.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767PubMedGoogle Scholar
  67. 67.
    Salahshor S, Kressner U, Pahlman L et al (1999) Colorectal cancer with and without microsatellite instability involves different genes. Genes Chromosomes Cancer 26:247–252PubMedGoogle Scholar
  68. 68.
    Andreyev HJ, Norman AR, Cunningham D et al (2001) Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 85:692–696PubMedGoogle Scholar
  69. 69.
    Almoguera C, Shibata D, Forrester K et al (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554PubMedGoogle Scholar
  70. 70.
    Hruban RH, van Mansfeld AD, Offerhaus GJ et al (1993) K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143:545–554PubMedGoogle Scholar
  71. 71.
    Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al (2007) 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 67:2643–2648PubMedGoogle Scholar
  72. 72.
    Lievre A, Bachet JB, Le Corre D et al (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995PubMedGoogle Scholar
  73. 73.
    Lievre A, Bachet JB, Boige V et al (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374–379PubMedGoogle Scholar
  74. 74.
    De Roock W, Piessevaux H, De Schutter J et al (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508–515Google Scholar
  75. 75.
    Di Fiore F, Blanchard F, Charbonnier F et al (2007) Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 96:1166–1169PubMedGoogle Scholar
  76. 76.
    Amado RG, Wolf M, Freeman D et al (2008) Panitumumab (pmab) efficacy and patient-reported outcomes (PRO) in metastatic colorectal cancer (mCRC) patients (pts) with wild-type (WT) KRAS tumor status. J Clin Oncol 26 (ASCO-GI Meeting): Abstract 278Google Scholar
  77. 77.
    Moriai T, Kobrin MS, Hope C et al (1994) A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci USA 91:10217–10221PubMedGoogle Scholar
  78. 78.
    Gebhardt F, Zanker KS, Brandt B (1999) Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 274:13176–13180PubMedGoogle Scholar
  79. 79.
    Bhowmick DA, Zhuang Z, Wait SD et al (2004) A functional polymorphism in the EGF gene is found with increased frequency in glioblastoma multiforme patients and is associated with more aggressive disease. Cancer Res 64:1220–1223PubMedGoogle Scholar
  80. 80.
    Spindler KL, Nielsen JN, Ornskov D et al (2007) Epidermal growth factor (EGF) A61G polymorphism and EGF gene expression in normal colon tissue from patients with colorectal cancer. Acta Oncol 46(8):1113–1117PubMedGoogle Scholar
  81. 81.
    Dannenberg AJ, Lippman SM, Mann JR et al (2005) Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 23:254–266PubMedGoogle Scholar
  82. 82.
    Papafili A, Hill MR, Brull DJ et al (2002) Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 22:1631–1636PubMedGoogle Scholar
  83. 83.
    Peng D, Fan Z, Lu Y et al (1996) Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res 56:3666–3669PubMedGoogle Scholar
  84. 84.
    Kalish LH, Kwong RA, Cole IE et al (2004) Deregulated cyclin D1 expression is associated with decreased efficacy of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in head and neck squamous cell carcinoma cell lines. Clin Cancer Res 10:7764–7774PubMedGoogle Scholar
  85. 85.
    Petty WJ, Dragnev KH, Memoli VA et al (2004) Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers. Clin Cancer Res 10:7547–7554PubMedGoogle Scholar
  86. 86.
    Betticher DC, Thatcher N, Altermatt HJ et al (1995) Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11:1005–1011PubMedGoogle Scholar
  87. 87.
    Izzo JG, Papadimitrakopoulou VA, Liu DD et al (2003) Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer. J Natl Cancer Inst 95:198–205PubMedCrossRefGoogle Scholar
  88. 88.
    Matthias C, Branigan K, Jahnke V et al (1998) Polymorphism within the cyclin D1 gene is associated with prognosis in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 4:2411–2418PubMedGoogle Scholar
  89. 89.
    Fan Z, Masui H, Altas I et al (1993) Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 53:4322–4328PubMedGoogle Scholar
  90. 90.
    Bier H, Hoffmann T, Haas I et al (1998) Anti-(epidermal growth factor) receptor monoclonal antibodies for the induction of antibody-dependent cell-mediated cytotoxicity against squamous cell carcinoma lines of the head and neck. Cancer Immunol Immunother 46:167–173PubMedGoogle Scholar
  91. 91.
    Manches O, Lui G, Chaperot L et al (2003) In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood 101:949–954PubMedGoogle Scholar
  92. 92.
    Clynes RA, Towers TL, Presta LG et al (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443–446PubMedGoogle Scholar
  93. 93.
    Shields RL, Namenuk AK, Hong K et al (2001) High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 276:6591–6604PubMedGoogle Scholar
  94. 94.
    Wu J, Edberg JC, Redecha PB et al (1997) A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 100:1059–1070PubMedGoogle Scholar
  95. 95.
    Zhang W, Gordon M, Schultheis AM et al (2007) FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 25:3712–3718PubMedGoogle Scholar
  96. 96.
    Dall’Ozzo S, Tartas S, Paintaud G et al (2004) Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration–effect relationship. Cancer Res 64:4664–4669PubMedGoogle Scholar
  97. 97.
    Louis E, El Ghoul Z, Vermeire S et al (2004) Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn’s disease. Aliment Pharmacol Ther 19:511–519PubMedGoogle Scholar
  98. 98.
    Vallböhmer D, Zhang W, Gordon M et al (2005) Molecular determinants of cetuximab efficacy. J Clin Oncol 23:3536–3544PubMedGoogle Scholar
  99. 99.
    Camp ER, Summy J, Bauer TW et al (2005) Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 11:397–405PubMedGoogle Scholar
  100. 100.
    Reinmuth N, Fan F, Liu W et al (2002) Impact of insulin-like growth factor receptor-I function on angiogenesis, growth, and metastasis of colon cancer. Lab Invest 82:1377–1389PubMedGoogle Scholar
  101. 101.
    Kulik G, Klippel A, Weber MJ (1997) Antiapoptotic signaling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol 17:1595–1606PubMedGoogle Scholar
  102. 102.
    Chakravarti A, Loeffler JS, Dyson NJ (2002) 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 62:200–207PubMedGoogle Scholar
  103. 103.
    Lu D, Zhang H, Ludwig D et al (2004) Simultaneous blockade of both the epidermal growth factor receptor and the insulin-like growth factor receptor signaling pathways in cancer cells with a fully human recombinant bispecific antibody. J Biol Chem 279:2856–2865PubMedGoogle Scholar
  104. 104.
    Jones HE, Goddard L, Gee JM et al (2004) Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814PubMedGoogle Scholar
  105. 105.
    Hennessy BT, Smith DL, Ram PT et al (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988–1004PubMedGoogle Scholar
  106. 106.
    Ali IU, Schriml LM, Dean M (1999) Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 91:1922–1932PubMedGoogle Scholar
  107. 107.
    Nassif NT, Lobo GP, Wu X et al (2004) PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene 23:617–628PubMedGoogle Scholar
  108. 108.
    Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501PubMedGoogle Scholar
  109. 109.
    Yu HG, Ai YW, Yu LL et al (2008) Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer 122:433–443PubMedGoogle Scholar
  110. 110.
    Mellinghoff IK, Cloughesy TF, Mischel PS (2007) PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res 13:378–381PubMedGoogle Scholar
  111. 111.
    Frattini M, Saletti P, Romagnani E et al (2007) PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139–1145PubMedGoogle Scholar
  112. 112.
    Nagata Y, Lan KH, Zhou X et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127PubMedGoogle Scholar
  113. 113.
    Parsons SJ, Parsons JT (2004) Src family kinases, key regulators of signal transduction. Oncogene 23:7906–7909PubMedGoogle Scholar
  114. 114.
    Tice DA, Biscardi JS, Nickles AL et al (1999) Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci USA 96:1415–1420PubMedGoogle Scholar
  115. 115.
    Ishizawar R, Parsons SJ (2004) c-Src and cooperating partners in human cancer. Cancer Cell 6:209–214PubMedGoogle Scholar
  116. 116.
    Hunter T (1987) A tail of two src’s: mutatis mutandis. Cell 49:1–4PubMedGoogle Scholar
  117. 117.
    Biscardi JS, Maa MC, Tice DA et al (1999) c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem 274:8335–8343PubMedGoogle Scholar
  118. 118.
    Kalyn R (2007) Overview of targeted therapies in oncology. J Oncol Pharm Pract 13:199–205PubMedGoogle Scholar
  119. 119.
    Mendelsohn J (2001) The epidermal growth factor receptor as a target for cancer therapy. Endocr Relat Cancer 8:3–9PubMedGoogle Scholar
  120. 120.
    Iqbal S, Goldman B, Lenz HJ et al (2007) S0413: a phase II SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer. J Clin Oncol 25:18SGoogle Scholar
  121. 121.
    Zhang W, Gordon M, Lenz HJ (2006) Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies. Ann Med 38:545–551PubMedGoogle Scholar
  122. 122.
    Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Philipp C. Manegold
    • 1
  • Georg Lurje
    • 1
  • Alexandra Pohl
    • 1
  • Yan Ning
    • 1
  • Wu Zhang
    • 1
  • Heinz-Josef Lenz
    • 1
    • 2
    • 3
  1. 1.Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Colorectal Cancer, Sharon A. Carpenter Laboratory, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

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