Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Understanding resistance to EGFR inhibitors—impact on future treatment strategies

Abstract

EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.

Key Points

  • EGFR has been the most comprehensively studied molecular target in oncology therapeutics over the past decade

  • Four primary EGFR inhibitors—gefitinib, cetuximab, erlotinib, and panitumumab—received FDA approval in oncology in the space of less than 4 years (2003–2006)

  • Current FDA-approved indications for primary EGFR inhibitors include selected patients with colorectal cancer, head and neck cancer, lung cancer and pancreatic cancer

  • EGFR mutations in a cohort of lung cancer patients and KRAS mutations in a cohort of colorectal cancer patients are powerful predictors of response to specific EGFR inhibitors

  • Intrinsic and acquired resistance to EGFR inhibitors is increasingly well recognized

  • A greater understanding of molecular mechanisms of resistance to EGFR inhibitors is stimulating new treatment strategies to enhance the impact of these promising agents

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: EGFR biology.
Figure 2: Mechanisms of resistance to EGFR antibodies.
Figure 3: Mechanisms of resistance to EGFR TKIs.

Similar content being viewed by others

References

  1. Cohen, S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J. Biol. Chem. 237, 1555–1562 (1962).

    CAS  PubMed  Google Scholar 

  2. Cohen, S. The stimulation of epidermal proliferation by a specific protein (EGF). Dev. Biol. 12, 394–407 (1965).

    Article  CAS  PubMed  Google Scholar 

  3. Carpenter, G., Lembach, K. J., Morrison, M. M. & Cohen, S. Characterization of the binding of 125I-labeled epidermal growth factor to human fibroblasts. J. Biol. Chem. 250, 4297–4304 (1975).

    CAS  PubMed  Google Scholar 

  4. Carpenter, G., King, L. Jr & Cohen, S. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro. Nature 276, 409–410 (1978).

    Article  CAS  PubMed  Google Scholar 

  5. Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309, 418–425 (1984).

    Article  CAS  PubMed  Google Scholar 

  6. Eckhart, W., Hutchinson, M. A. & Hunter, T. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell 18, 925–933 (1979).

    Article  CAS  PubMed  Google Scholar 

  7. Hunter, T. & Sefton, B. M. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl Acad. Sci. USA 77, 1311–1315 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Marmor, M. D., Skaria, K. B. & Yarden, Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int. J. Radiat. Oncol. Biol. Phys. 58, 903–913 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Libermann, T. A. et al. Expression of epidermal growth factor receptors in human brain tumors. Cancer Res. 44, 753–760 (1984).

    CAS  PubMed  Google Scholar 

  11. Libermann, T. A. et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313, 144–147 (1985).

    Article  CAS  PubMed  Google Scholar 

  12. Libermann, T. A. et al. Amplification and overexpression of the EGF receptor gene in primary human glioblastomas. J. Cell Sci. Suppl. 3, 161–172 (1985).

    Article  CAS  PubMed  Google Scholar 

  13. Veale, D., Ashcroft, T., Marsh, C., Gibson, G. J. & Harris, A. L. Epidermal growth factor receptors in non-small cell lung cancer. Br. J. Cancer 55, 513–516 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Weichselbaum, R. R. et al. Epidermal growth factor receptor gene amplification and expression in head and neck cancer cell lines. Head Neck 11, 437–442 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Sato, J. D. et al. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol. Biol. Med. 1, 511–529 (1983).

    CAS  PubMed  Google Scholar 

  16. Kawamoto, T. et al. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc. Natl Acad. Sci. USA 80, 1337–1341 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Honegger, A. M. et al. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell 51, 199–209 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Honegger, A. M. et al. A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol. Cell. Biol. 7, 4568–4571 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Redemann, N. et al. Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants. Mol. Cell. Biol. 12, 491–498 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fry, D. W. et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265, 1093–1095 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Osherov, N. & Levitzki, A. Epidermal-growth-factor-dependent activation of the src-family kinases. Eur. J. Biochem. 225, 1047–1053 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Wakeling, A. E. et al. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res. Treat. 38, 67–73 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Bonner, J. A. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354, 567–578 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Herbst, R. S. et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J. Clin. Oncol. 22, 785–794 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Thatcher, N. et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366, 1527–1537 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Borner, M. et al. Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK. Ann. Oncol. 19, 1288–1292 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Sobrero, A. F. et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 2311–2319 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Moore, M. J. 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. 25, 1960–1966 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Senderowicz, A. M. et al. Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. Oncology (Williston Park) 21, 1696–1706 (2007).

    Google Scholar 

  30. Di Leo, A. et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J. Clin. Oncol. 26, 5544–5552 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jackman, D. et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J. Clin. Oncol. 28, 357–360 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Hynes, N. E. & Lane, H. A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 5, 341–354 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Klapper, L. N. et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc. Natl Acad. Sci. USA 96, 4995–5000 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baselga, J. & Swain, S. M. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9, 463–475 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Guy, P. M., Platko, J. V., Cantley, L. C., Cerione, R. A. & Carraway, K. L. 3rd. Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc. Natl Acad. Sci. USA 91, 8132–8136 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wallasch, C. et al. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J. 14, 4267–4275 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Weihua, Z. et al. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 13, 385–393 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Marti, U. et al. Localization of epidermal growth factor receptor in hepatocyte nuclei. Hepatology 13, 15–20 (1991).

    Article  CAS  PubMed  Google Scholar 

  39. Cao, H., Lei, Z. M., Bian, L. & Rao, C. V. Functional nuclear epidermal growth factor receptors in human choriocarcinoma JEG-3 cells and normal human placenta. Endocrinology 136, 3163–3172 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Lin, S. Y. et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat. Cell Biol. 3, 802–808 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Lo, H. W., Hsu, S. C. & Hung, M. C. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res. Treat. 95, 211–218 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Lo, H. W. & Hung, M. C. Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br. J. Cancer 94, 184–188 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lo, H. W. et al. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res. 65, 338–348 (2005).

    CAS  PubMed  Google Scholar 

  44. Psyrri, A. et al. Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis. Clin. Cancer Res. 11, 5856–5862 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Xia, W. et al. Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer. Mol. Carcinog. 48, 610–617 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hanada, N. et al. Co-regulation of B-Myb expression by E2F1 and EGF receptor. Mol. Carcinog. 45, 10–17 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Lo, H. W. et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 7, 575–589 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Lo, H. W., Cao, X., Zhu, H. & Ali-Osman, F. Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes. Mol. Cancer Res. 8, 232–245 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hsu, S. C. & Hung, M. C. Characterization of a novel tripartite nuclear localization sequence in the EGFR family. J. Biol. Chem. 282, 10432–10440 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Lo, H. W. et al. Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1. J. Cell. Biochem. 98, 1570–1583 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Liao, H. J. & Carpenter, G. Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression. Mol. Biol. Cell 18, 1064–1072 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hung, L. Y. et al. Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression. Nucleic Acids Res. 36, 4337–4351 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, S. C. et al. Tyrosine phosphorylation controls PCNA function through protein stability. Nat. Cell Biol. 8, 1359–1368 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Goldstein, N. I., Prewett, M., Zuklys, K., Rockwell, P. & Mendelsohn, J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin. Cancer Res. 1, 1311–1318 (1995).

    CAS  PubMed  Google Scholar 

  55. Kimura, H. et al. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 98, 1275–1280 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Saltz, L. B. et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J. Clin. Oncol. 25, 4557–4561 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Jonker, D. J. et al. Cetuximab for the treatment of colorectal cancer. N. Engl. J. Med. 357, 2040–2048 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Vermorken, J. B. et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359, 1116–1127 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Burtness, B., Goldwasser, M. A., Flood, W., Mattar, B. & Forastiere, A. A. 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, 8646–8654 (2005).

    Article  PubMed  Google Scholar 

  62. Yang, X. D., Jia, X. C., Corvalan, J. R., Wang, P. & Davis, C. G. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit. Rev. Oncol. Hematol. 38, 17–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Yang, X. D. et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 59, 1236–1243 (1999).

    CAS  PubMed  Google Scholar 

  64. Hecht, J. R. et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J. Clin. Oncol. 27, 672–680 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Giusti, R. M. et al. U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clin. Cancer Res. 14, 1296–1302 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Van Cutsem, E. et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Kris, M. G. et al. 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, 2149–2158 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Fukuoka, M. et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J. Clin. Oncol. 21, 2237–2246 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Giaccone, G. et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J. Clin. Oncol. 22, 777–784 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Herbst, R. S. et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J. Clin. Oncol. 23, 5892–5899 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Gatzemeier, U. et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J. Clin. Oncol. 25, 1545–1552 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Shepherd, F. A. et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Tsao, M. S. et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N. Engl. J. Med. 353, 133–144 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Kwak, E. L. et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl Acad. Sci. USA 102, 7665–7670 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Asahina, H. et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br. J. Cancer 95, 998–1004 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Inoue, A. et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J. Clin. Oncol. 27, 1394–1400 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Inoue, A. et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J. Clin. Oncol. 24, 3340–3346 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Rosell, R. et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361, 958–967 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Sequist, L. V. et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J. Clin. Oncol. 26, 2442–2449 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. van Zandwijk, N. et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann. Oncol. 18, 99–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Yoshida, K. et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J. Thorac. Oncol. 2, 22–28 (2007).

    Article  PubMed  Google Scholar 

  87. Butts, C. A. et al. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J. Clin. Oncol. 25, 5777–5784 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Herbst, R. S. et al. A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342 [abstract]. J. Clin. Oncol. 25, 7545 (2007).

    Article  CAS  Google Scholar 

  89. Robert, F. et al. Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. J. Clin. Oncol. 23, 9089–9096 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Rosell, R. et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann. Oncol. 19, 362–369 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Thienelt, C. D. et al. Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J. Clin. Oncol. 23, 8786–8793 (2005).

    Article  PubMed  Google Scholar 

  92. Pirker, R. et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373, 1525–1531 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Lynch, T. J. et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J. Clin. Oncol. 28, 911–917 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Robert, F. et al. Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J. Clin. Oncol. 19, 3234–3243 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Bokemeyer, C. et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 27, 663–671 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Lièvre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66, 3992–3995 (2006).

    Article  PubMed  Google Scholar 

  97. Di Fiore, F. et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br. J. Cancer 96, 1166–1169 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. De Roock, W. et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol. 19, 508–515 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Bokemeyer, C. et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience [abstract]. J. Clin. Oncol. 26, 4000 (2008).

  102. Van Cutsem, E. et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience [abstract]. J. Clin. Oncol. 26, 2 (2008).

  103. Punt, C. J. & Tol, J. More is less—combining targeted therapies in metastatic colorectal cancer. Nat. Rev. Clin. Oncol. 6, 731–733 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Chung, K. Y. et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J. Clin. Oncol. 23, 1803–1810 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Lenz, H. J. et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J. Clin. Oncol. 24, 4914–4921 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Moroni, M. et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 6, 279–286 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Sartore-Bianchi, A. et al. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J. Clin. Oncol. 25, 3238–3245 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Punt, C. J. et al. Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG) [abstract]. J. Clin. Oncol. 26, LBA4011 (2008).

    Article  Google Scholar 

  109. Allegra, C. J. et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol. 27, 2091–2096 (2009).

    Article  PubMed  Google Scholar 

  110. Khambata-Ford, S. et al. 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, 3230–3237 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Jacobs, B. et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J. Clin. Oncol. 27, 5068–5074 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Mukohara, T. et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J. Natl Cancer Inst. 97, 1185–1194 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Goldman, C. K. et al. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol. Biol. Cell 4, 121–133 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ciardiello, F. et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin. Cancer Res. 7, 1459–1465 (2001).

    CAS  PubMed  Google Scholar 

  115. Viloria-Petit, A. et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 61, 5090–5101 (2001).

    CAS  PubMed  Google Scholar 

  116. Ciardiello, F. et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin. Cancer Res. 10, 784–793 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Wheeler, D. L. et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27, 3944–3956 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Huang, S., Armstrong, E. A., Benavente, S., Chinnaiyan, P. & Harari, P. M. Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res. 64, 5355–5362 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Matar, P. et al. Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin. Cancer Res. 10, 6487–6501 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Bianco, R. et al. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin. Cancer Res. 14, 5069–5080 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Sok, J. C. et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin. Cancer Res. 12, 5064–5073 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Lu, Y. et al. Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. Cancer Res. 67, 8240–8247 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Wheeler, D. L. et al. Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab. Cancer Biol. Ther. 8, 696–703 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Wang, S. C. & Hung, M. C. Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clin. Cancer Res. 15, 6484–6489 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Li, C., Iida, M., Dunn, E. F., Ghia, A. J. & Wheeler, D. L. Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene 28, 3801–3813 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nevo, J. et al. Mammary-derived growth inhibitor alters traffic of EGFR and induces a novel form of cetuximab resistance. Clin. Cancer Res. 15, 6570–6581 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Fuchs, B. C. et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res. 68, 2391–2399 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Yun, C. H. et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl Acad. Sci. USA 105, 2070–2075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kosaka, T. et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 64, 8919–8923 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Gow, C. H., Shih, J. Y., Chang, Y. L. & Yu, C. J. Acquired gefitinib-resistant mutation of EGFR in a chemonaive lung adenocarcinoma harboring gefitinib-sensitive mutation L858R. PLoS Med. 2, e269 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Kwak, E. L. et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin. Cancer Res. 12, 4283–4287 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bell, D. W. et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat. Genet. 37, 1315–1316 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Shih, J. Y., Gow, C. H. & Yang, P. C. EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N. Engl. J. Med. 353, 207–208 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Rodenhuis, S. et al. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N. Engl. J. Med. 317, 929–935 (1987).

    Article  CAS  PubMed  Google Scholar 

  135. Mitsudomi, T. et al. ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res. 51, 4999–5002 (1991).

    CAS  PubMed  Google Scholar 

  136. Husgafvel-Pursiainen, K. et al. K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos. Int. J. Cancer 53, 250–256 (1993).

    Article  CAS  PubMed  Google Scholar 

  137. Ahrendt, S. A. et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 92, 1525–1530 (2001).

    Article  CAS  PubMed  Google Scholar 

  138. Pao, W. et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2, e17 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Learn, C. A. et al. Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme. Clin. Cancer Res. 10, 3216–3224 (2004).

    Article  CAS  PubMed  Google Scholar 

  140. Erjala, K. et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin. Cancer Res. 12, 4103–4111 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Zhou, B. B. et al. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell 10, 39–50 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kohno, T., Takahashi, M., Manda, R. & Yokota, J. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer 22, 152–156 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Soria, J. C. et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin. Cancer Res. 8, 1178–1184 (2002).

    CAS  PubMed  Google Scholar 

  144. She, Q. B., Solit, D., Basso, A. & Moasser, M. M. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin. Cancer Res. 9, 4340–4346 (2003).

    CAS  PubMed  Google Scholar 

  145. Bianco, R. et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22, 2812–2822 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Cappuzzo, F. et al. Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib. Ann. Oncol. 17, 1120–1127 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Engelman, J. A. et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl Acad. Sci. USA 102, 3788–3793 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Yano, S. et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 68, 9479–9487 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer 8, 915–928 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. Chakravarti, A., Loeffler, J. S. & Dyson, N. J. 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, 200–207 (2002).

    CAS  PubMed  Google Scholar 

  152. Guix, M. et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J. Clin. Invest. 118, 2609–2619 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Russo, M. W., Lukas, T. J., Cohen, S. & Staros, J. V. Identification of residues in the nucleotide binding site of the epidermal growth factor receptor/kinase. J. Biol. Chem. 260, 5205–5208 (1985).

    CAS  PubMed  Google Scholar 

  154. Gullick, W. J., Downward, J., Foulkes, J. G. & Waterfield, M. D. Antibodies to the ATP-binding site of the human epidermal growth factor (EGF) receptor as specific inhibitors of EGF-stimulated protein-tyrosine kinase activity. Eur. J. Biochem. 158, 245–253 (1986).

    Article  CAS  PubMed  Google Scholar 

  155. Biscardi, J. S. et al. 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, 8335–8343 (1999).

    Article  CAS  PubMed  Google Scholar 

  156. Grøvdal, L. M., Stang, E., Sorkin, A. & Madshus, I. H. Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation. Exp. Cell Res. 300, 388–395 (2004).

    Article  PubMed  CAS  Google Scholar 

  157. Buday, L. & Downward, J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73, 611–620 (1993).

    Article  CAS  PubMed  Google Scholar 

  158. Keilhack, H. et al. Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling. J. Biol. Chem. 273, 24839–24846 (1998).

    Article  CAS  PubMed  Google Scholar 

  159. Dittmann, K., Mayer, C., Kehlbach, R. & Rodemann, H. P. Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK. Mol. Cancer 7, 69 (2008).

  160. Rajput, A. et al. A novel mechanism of resistance to epidermal growth factor receptor antagonism in vivo. Cancer Res. 67, 665–673 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Batra, S. K. et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ. 6, 1251–1259 (1995).

    CAS  PubMed  Google Scholar 

  162. Wong, S. F. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin. Ther. 27, 684–694 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Li, S. et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7, 301–311 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Baselga, J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur. J. Cancer 37, S16–S22 (2001).

    Article  CAS  PubMed  Google Scholar 

  165. Kurai, J. et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin. Cancer Res. 13, 1552–1561 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Martinelli, E., De Palma, R., Orditura, M., De Vita, F. & Ciardiello, F. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin. Exp. Immunol. 158, 1–9 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Mandal, M., Adam, L., Mendelsohn, J. & Kumar, R. Nuclear targeting of Bax during apoptosis in human colorectal cancer cells. Oncogene 17, 999–1007 (1998).

    Article  CAS  PubMed  Google Scholar 

  168. Liu, B. et al. Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br. J. Cancer 82, 1991–1999 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Dittmann, K., Mayer, C. & Rodemann, H. Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity. Radiother. Oncol. 76, 157–161 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Huang, S., Bock, J. M. & Harari, P. M. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 59, 1935–1940 (1999).

    CAS  PubMed  Google Scholar 

  171. Campiglio, M. et al. Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level. J. Cell. Physiol. 198, 259–268 (2004).

    Article  CAS  PubMed  Google Scholar 

  172. Moasser, M. M., Basso, A., Averbuch, S. D. & Rosen, N. The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 61, 7184–7188 (2001).

    CAS  PubMed  Google Scholar 

  173. Moulder, S. L. et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res. 61, 8887–8895 (2001).

    CAS  PubMed  Google Scholar 

  174. Normanno, N. et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann. Oncol. 13, 65–72 (2002).

    Article  CAS  PubMed  Google Scholar 

  175. Schaefer, G., Shao, L., Totpal, K. & Akita, R. W. Erlotinib directly inhibits HER2 kinase activation and downstream signaling events in intact cells lacking epidermal growth factor receptor expression. Cancer Res. 67, 1228–1238 (2007).

    Article  CAS  PubMed  Google Scholar 

  176. Lichtner, R. B., Menrad, A., Sommer, A., Klar, U. & Schneider, M. R. Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline tyrosine kinase inhibitors. Cancer Res. 61, 5790–5795 (2001).

    CAS  PubMed  Google Scholar 

  177. Baselga, 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 platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J. Clin. Oncol. 23, 5568–5577 (2005).

    Article  CAS  PubMed  Google Scholar 

  178. Herbst, R. S. 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. 23, 5578–5587 (2005).

    Article  CAS  PubMed  Google Scholar 

  179. Geyer, C. E. et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733–2743 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The laboratory of P. M. Harari is supported in part by the NIH/NCI Grant R01 CA113448. The laboratory of D. L. Wheeler is supported in part by NIH grant P30CAO14520. E. F. Dunn is supported by an NIH T32 grant (Grant CA009614-17 Physician Scientist Training in Cancer Medicine).

Author information

Authors and Affiliations

Authors

Contributions

D. L. Wheeler, E. F. Dunn and P. M. Harari contributed equally to the researching and writing of this manuscript.

Corresponding author

Correspondence to Deric L. Wheeler.

Ethics declarations

Competing interests

D. L. Wheeler has received grant/research support from Bristol-Myers Squibb. P. M. Harari has received grant/research support from Amgen, AstraZeneca, Genentech and ImClone. E. F. Dunn declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wheeler, D., Dunn, E. & Harari, P. Understanding resistance to EGFR inhibitors—impact on future treatment strategies. Nat Rev Clin Oncol 7, 493–507 (2010). https://doi.org/10.1038/nrclinonc.2010.97

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2010.97

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing