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:

The quest to overcome resistance to EGFR-targeted therapies in cancer

Abstract

All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.

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 signaling pathways.
Figure 2: Timeline of key discoveries in the EGFR field.
Figure 3: Clinically validated resistance mechanisms to EGFR inhibitors.
Figure 4: Efficacy of targeted therapies in cancer treatment.

Similar content being viewed by others

References

  1. Cataldo, V.D., Gibbons, D.L., Perez-Soler, R. & Quintas-Cardama, A. Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N. Engl. J. Med. 364, 947–955 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Ciardiello, F. & Tortora, G. EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160–1174 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Mitsudomi, T. & Yatabe, Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 277, 301–308 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Weinstein, I.B. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Campoli, M., Ferris, R., Ferrone, S. & Wang, X. Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies. Clin. Cancer Res. 16, 11–20 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Yun, C.H. et al. Structures of lung cancer–derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11, 217–227 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Greulich, H. et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2, e313 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yeh, P. et al. DNA-mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT): a catalog of clinically relevant cancer mutations to enable genome-directed anticancer therapy. Clin. Cancer Res. 19, 1894–1901 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oxnard, G.R. et al. Screening for germline EGFR T790M mutations through lung cancer genotyping. J. Thorac. Oncol. 7, 1049–1052 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Zhou, C. et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12, 735–742 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13, 239–246 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Mitsudomi, T. et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 11, 121–128 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. Douillard, J.Y. et al. 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, 4697–4705 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Peeters, M. et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J. Clin. Oncol. 28, 4706–4713 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Van Cutsem, E. et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol. 29, 2011–2019 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Ardito, C.M. et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Navas, C. et al. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Budha, N.R. et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin. Pharmacol. Ther. 92, 203–213 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Mir, O., Blanchet, B. & Goldwasser, F. Drug-induced effects on erlotinib metabolism. N. Engl. J. Med. 365, 379–380 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Wheeler, D.L., Dunn, E.F. & Harari, P.M. Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat. Rev. Clin. Oncol. 7, 493–507 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ng, K.P. et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat. Med. 18, 521–528 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Yu, H.A. et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 19, 2240–2247 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee, J.K. et al. Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study. Ann. Oncol. 24, 2080–2087 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Gorre, M.E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Heinrich, M.C. et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J. Clin. Oncol. 24, 4764–4774 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Choi, Y.L. et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N. Engl. J. Med. 363, 1734–1739 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Bresler, S.C. et al. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci. Transl. Med. 3, 108ra114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 

  40. Chmielecki, J. et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci. Transl. Med. 3, 90ra59 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Inukai, M. et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res. 66, 7854–7858 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Montagut, C. et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat. Med. 18, 221–223 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Gottesman, M.M. Mechanisms of cancer drug resistance. Annu. Rev. Med. 53, 615–627 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Takezawa, K. et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2, 922–933 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yonesaka, K. et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3, 99ra86 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Laurent-Puig, P. et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J. Clin. Oncol. 27, 5924–5930 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Sartore-Bianchi, A. et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS ONE 4, e7287 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Diaz, L.A. Jr. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ohashi, K. et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc. Natl. Acad. Sci. USA 109, E2127–E2133 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sartore-Bianchi, A. et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 69, 1851–1857 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Corcoran, R.B. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAFV600E inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Janne, P.A. et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J. Clin. Oncol. 30, 2063–2069 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Thomson, S. et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 65, 9455–9462 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Uramoto, H. et al. Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res. 30, 2513–2517 (2010).

    CAS  PubMed  Google Scholar 

  58. Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44, 852–860 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xie, M. et al. Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J. Cell Biochem. 113, 1501–1513 (2012).

    CAS  PubMed  Google Scholar 

  60. Yao, Z. et al. TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc. Natl. Acad. Sci. USA 107, 15535–15540 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Alam, N. et al. Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. Clin. Lung Cancer 11, E1–E4 (2010).

    Article  PubMed  Google Scholar 

  62. 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 

  63. Sos, M.L. et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 69, 3256–3261 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Suda, K. et al. Conversion from the “oncogene addiction” to “drug addiction” by intensive inhibition of the EGFR and MET in lung cancer with activating EGFR mutation. Lung Cancer 76, 292–299 (2012).

    Article  PubMed  Google Scholar 

  65. Cheung, H.W. et al. Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers. Cancer Discov. 1, 608–625 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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 

  67. Wang, S.E. et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10, 25–38 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Terai, H. et al. Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC cells. Mol. Cancer Res. 11, 759–767 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Ware, K.E. et al. A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis 2, e39 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ware, K.E. et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS ONE 5, e14117 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Harada, D. et al. JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. Cancer Sci. 103, 1795–1802 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Shien, K. et al. Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell–like properties in cancer cells. Cancer Res. 73, 3051–3061 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mink, S.R. et al. Cancer-associated fibroblasts derived from EGFR-TKI–resistant tumors reverse EGFR pathway inhibition by EGFR-TKIs. Mol. Cancer Res. 8, 809–820 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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 

  76. Garofalo, M. et al. EGFR and MET receptor tyrosine kinase–altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat. Med. 18, 74–82 (2012).

    Article  CAS  Google Scholar 

  77. Rai, K. et al. Liposomal delivery of microRNA-7–expressing plasmid overcomes epidermal growth factor receptor tyrosine kinase inhibitor-resistance in lung cancer cells. Mol. Cancer Ther. 10, 1720–1727 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Sharma, S.V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Garraway, L.A. & Janne, P.A. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2, 214–226 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Bridges, A.J. The rationale and strategy used to develop a series of highly potent, irreversible, inhibitors of the epidermal growth factor receptor family of tyrosine kinases. Curr. Med. Chem. 6, 825–843 (1999).

    CAS  PubMed  Google Scholar 

  81. Kwak, E. The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer. Oncologist 16, 1498–1507 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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 

  83. 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 

  84. Zhou, W. et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462, 1070–1074 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dienstmann, R., De Dosso, S., Felip, E. & Tabernero, J. Drug development to overcome resistance to EGFR inhibitors in lung and colorectal cancer. Mol. Oncol. 6, 15–26 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Yu, H.A. & Riely, G.J. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers. J. Natl. Compr. Canc. Netw. 11, 161–169 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ranson, M. et al. Preliminary results from a Phase I study with AZD9291: an irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance mutations in non-small cell lung cancer (NSCLC). European Cancer Conference (Amsterdam, 2013).

  88. Ou, S.H. Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a better mousetrap? A review of the clinical evidence. Crit. Rev. Oncol. Hematol. 83, 407–421 (2012).

    Article  PubMed  Google Scholar 

  89. Lee, H.J. et al. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov. 3, 168–181 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Rivera, V.M. et al. AP26113 is a dual ALK/EGFR inhibitor: characterization against EGFR T790M in cell and mouse models of NSCLC. Cancer Res. 72 (suppl. 1), abstract 1794 (2012).

    Google Scholar 

  91. Red Brewer, M. & Pao, W. Maximizing the benefits of off-target kinase inhibitor activity. Cancer Discov. 3, 138–140 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Yang, J.C., Schuler, M.H., Yamamoto, N., O'Byrne, K.J. & Hirsh, V. LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J. Clin. Oncol. 30, LBA7500 (2012).

    Article  Google Scholar 

  93. Atagi, S., Katakami, N., Hida, T., Goto, K. & Horai, T. LUX-Lung 4: a phase II trial of afatinib (BIBW 2992) in advanced NSCLC patients previously treated with erlotinib or gefitinib. 14th World Conference on Lung Cancer (Amsterdam, 2011).

  94. Ercan, D. et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 29, 2346–2356 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Godin-Heymann, N. et al. The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol. Cancer Ther. 7, 874–879 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Regales, L. et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J. Clin. Invest. 119, 3000–3010 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Janjigian, Y. et al. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J. Clin. Oncol. 29, 7525 (2011).

    Article  Google Scholar 

  98. Janjigian, Y.Y. et al. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin. Cancer Res. 17, 2521–2527 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Weickhardt, A.J. et al. Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. J. Clin. Oncol. 30, 1505–1512 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Abdul Razak, A.R. et al. A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Ann. Oncol. 24, 761–769 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Seiwert, T. et al. A randomized, open-label, phase II study Of afatinib (bibw 2992) versus cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck—final data. Multidisciplinary Head and Neck Symposium presentation LBPV10 (2012).

  102. Robinson, K.W. & Sandler, A.B. The role of MET receptor tyrosine kinase in non-small cell lung cancer and clinical development of targeted anti-MET agents. Oncologist 18, 115–122 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Johnson, M.L. et al. Phase II trial of dasatinib for patients with acquired resistance to treatment with the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib or gefitinib. J. Thorac. Oncol. 6, 1128–1131 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Riely, G.J. et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin. Cancer Res. 13, 5150–5155 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Lynch, T.J. et al. A randomized phase 2 study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer. J. Thorac. Oncol. 4, 1002–1009 (2009).

    Article  PubMed  Google Scholar 

  106. Herbst, R.S. et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 377, 1846–1854 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Scagliotti, G.V. et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J. Clin. Oncol. 30, 2070–2078 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Sequist, L.V. et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J. Clin. Oncol. 29, 3307–3315 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Wakelee, H.A. et al. A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib in patients (pts) with non-small cell lung cancer (NSCLC). J. Clin. Oncol. 28 (suppl. 15), abstract 3017 (2010).

    Article  Google Scholar 

  110. Ohashi, K., Maruvka, Y.E., Michor, F. & Pao, W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J. Clin. Oncol. 31, 1070–1080 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Topalian, S.L. et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gentile, A., Lazzari, L., Benvenuti, S., Trusolino, L. & Comoglio, P.M. Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 71, 3132–3141 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Yamaguchi, T. et al. NKX2–1/TITF1/TTF-1–induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell 21, 348–361 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Bean, G.R. et al. PUMA and BIM are required for oncogene inactivation-induced apoptosis. Sci. Signal. 6, ra20 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bock, C. & Lengauer, T. Managing drug resistance in cancer: lessons from HIV therapy. Nat. Rev. Cancer 12, 494–501 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Chmielecki, J. & Pao, W. Highly active antitumor therapy (HAATT) for epidermal growth factor receptor–mutant lung cancer. Clin. Cancer Res. 16, 5371–5373 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Suda, K. et al. Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer. Clin. Cancer Res. 16, 5489–5498 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA 104, 20932–20937 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Taniguchi, K., Okami, J., Kodama, K., Higashiyama, M. & Kato, K. Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib. Cancer Sci. 99, 929–935 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Park, S. et al. Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumors and lymph node metastasis in non-small cell lung cancer. J. Thorac. Oncol. 4, 809–815 (2009).

    Article  PubMed  Google Scholar 

  121. Chen, Z.Y. et al. EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas. Oncologist 17, 978–985 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Yatabe, Y., Matsuo, K. & Mitsudomi, T. Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma. J. Clin. Oncol. 29, 2972–2977 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Linardou, H. et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 9, 962–972 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Sun, L. et al. Comparison of KRAS and EGFR gene status between primary non-small cell lung cancer and local lymph node metastases: implications for clinical practice. J. Exp. Clin. Cancer Res. 30, 30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Pao, W. & Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat. Rev. Cancer 10, 760–774 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kim, E.S. et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44–53 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kuang, Y. et al. Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin. Cancer Res. 15, 2630–2636 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Maheswaran, S. et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359, 366–377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Forshew, T. et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci. Transl. Med. 4, 136ra168 (2012).

    Article  CAS  Google Scholar 

  130. Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Box, C. et al. A novel serum protein signature associated with resistance to epidermal growth factor receptor tyrosine kinase inhibitors in head and neck squamous cell carcinoma. Eur. J. Cancer 49, 2512–2521 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Taguchi, F. et al. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J. Natl. Cancer Inst. 99, 838–846 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Milton, D.T. et al. Molecular on/off switch. J. Clin. Oncol. 24, 4940–4942 (2006).

    Article  PubMed  Google Scholar 

  135. Chaft, J.E. et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin. Cancer Res. 17, 6298–6303 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Becker, A. et al. Retreatment with erlotinib: regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. Eur. J. Cancer 47, 2603–2606 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Oxnard, G.R. et al. Maintained sensitivity to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer recurring after adjuvant erlotinib or gefitinib. Clin. Cancer Res. 17, 6322–6328 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Foo, J., Chmielecki, J., Pao, W. & Michor, F. Effects of pharmacokinetic processes and varied dosing schedules on the dynamics of acquired resistance to erlotinib in EGFR-mutant lung cancer. J. Thorac. Oncol. 7, 1583–1593 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kuiper, J.L. & Smit, E.F. High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases—one with a remarkable thoracic response as well. Lung Cancer 80, 102–105 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Guilhot, F. et al. Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial. Haematologica 97, 731–738 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Larson, R.A. et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111, 4022–4028 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Fausto, P., Karen, B., Mary, C., Lonati, V. & Sandro, B. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer 78, 8–15 (2012).

    Article  Google Scholar 

  143. Liu, H.B. et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS ONE 8, e55128 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Sledge, G.W. Jr. The challenge and promise of the genomic era. J. Clin. Oncol. 30, 203–209 (2012).

    Article  PubMed  Google Scholar 

  145. 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 

  146. Hunter, T. & Cooper, J.A. Epidermal growth factor induces rapid tyrosine phosphorylation of proteins in A431 human tumor cells. Cell 24, 741–752 (1981).

    Article  CAS  PubMed  Google Scholar 

  147. 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 

  148. 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 

  149. 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 

  150. Downward, J. et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307, 521–527 (1984).

    Article  CAS  PubMed  Google Scholar 

  151. Kamata, T. & Feramisco, J.R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310, 147–150 (1984).

    Article  CAS  PubMed  Google Scholar 

  152. King, C.R., Kraus, M.H. & Aaronson, S.A. Amplification of a novel v-erbB–related gene in a human mammary carcinoma. Science 229, 974–976 (1985).

    Article  CAS  PubMed  Google Scholar 

  153. Gschwind, A., Fischer, O.M. & Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 4, 361–370 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Wong, A.J. et al. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc. Natl. Acad. Sci. USA 84, 6899–6903 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nicholson, R.I., Gee, J.M. & Harper, M.E. EGFR and cancer prognosis. Eur. J. Cancer 37 (suppl. 4), S9–S15 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. 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 

  157. 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 

  158. 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 

  159. 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 

  160. 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 

  161. 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  CAS  PubMed  PubMed Central  Google Scholar 

  162. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mok, T.S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Kantarjian, H. et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346, 645–652 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Tallman, M.S. et al. All-trans-retinoic acid in acute promyelocytic leukemia. N. Engl. J. Med. 337, 1021–1028 (1997).

    Article  CAS  PubMed  Google Scholar 

  167. Sosman, J.A. et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366, 707–714 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Blanke, C.D. et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J. Clin. Oncol. 26, 620–625 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Kwak, E.L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Fukuoka, M. et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J. Clin. Oncol. 29, 2866–2874 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Jackman, D.M. et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin. Cancer Res. 15, 5267–5273 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Won, Y.W. et al. Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations. J. Clin. Pathol. 64, 947–952 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. Chung, K.P. et al. Clinical outcomes in non-small cell lung cancers harboring different exon 19 deletions in EGFR. Clin. Cancer Res. 18, 3470–3477 (2012).

    Article  CAS  PubMed  Google Scholar 

  174. Riely, G.J. et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin. Cancer Res. 12, 839–844 (2006).

    Article  CAS  PubMed  Google Scholar 

  175. Arcila, M.E. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol. Cancer Ther. 12, 220–229 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Oxnard, G.R. et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J. Thorac. Oncol. 8, 179–184 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Arcila, M.E. et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol. Cancer Ther. 12, 220–229 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mitsudomi, T. & Yatabe, Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci. 98, 1817–1824 (2007).

    Article  CAS  PubMed  Google Scholar 

  179. Wu, J.Y. et al. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin. Cancer Res. 17, 3812–3821 (2011).

    Article  CAS  PubMed  Google Scholar 

  180. He, M. et al. EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma. Clin. Cancer Res. 18, 1790–1797 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. 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 

  182. Ogawa, T. et al. Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance. Cell Cycle 11, 1656–1663 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Cortot, A.B. et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res. 73, 834–843 (2013).

    Article  CAS  PubMed  Google Scholar 

  184. 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 

  185. Huang, S. et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 151, 937–950 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Bivona, T.G. et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523–526 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Naumov, G.N. et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin. Cancer Res. 15, 3484–3494 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Zakowski, M.F., Ladanyi, M. & Kris, M.G. EGFR mutations in small-cell lung cancers in patients who have never smoked. N. Engl. J. Med. 355, 213–215 (2006).

    Article  CAS  PubMed  Google Scholar 

  189. Scartozzi, M. et al. Correlation of insulin-like growth factor 1 (IGF-1) expression and clinical outcome in K-RAS wild-type colorectal cancer patients treated with cetuximab-irinotecan. J. Clin. Oncol. 27 (suppl. 15), abstract 4017 (2009).

    Google Scholar 

  190. Liska, D., Chen, C.T., Bachleitner-Hofmann, T., Christensen, J.G. & Weiser, M.R. HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin. Cancer Res. 17, 472–482 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Hoellein, A. et al. Aurora kinase inhibition overcomes cetuximab resistance in squamous cell cancer of the head and neck. Oncotarget. 2, 599–609 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  192. 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 

  193. Holz, C. et al. Epithelial-mesenchymal-transition induced by EGFR activation interferes with cell migration and response to irradiation and cetuximab in head and neck cancer cells. Radiother. Oncol. 101, 158–164 (2011).

    Article  CAS  PubMed  Google Scholar 

  194. La Fleur, L., Johansson, A.C. & Roberg, K.A. CD44high/EGFRlow subpopulation within head and neck cancer cell lines shows an epithelial-mesenchymal transition phenotype and resistance to treatment. PLoS ONE 7, e44071 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study is supported by US National Institutes of Health grants RO1CA114465 (P.A.J.), R01CA135257 (P.A.J.) and P01CA154303 (P.A.J.) and by an American Society of Clinical Oncology Young Investigator Award (C.R.C.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pasi A Jänne.

Ethics declarations

Competing interests

P.A.J. has received consulting fees from Astra-Zeneca, Boehringer Ingelheim, Clovis Oncology and Pfizer. P.A.J. also receives after-marketing royalties from Dana-Farber Cancer Institute on owned intellectual property regarding EGFR mutations.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4 (PDF 856 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chong, C., Jänne, P. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 19, 1389–1400 (2013). https://doi.org/10.1038/nm.3388

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3388

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