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Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer

Key Points

  • Epidermal growth factor receptor (EGFR)-mutant tumours define a unique subset of non-small-cell lung cancer (NSCLC). These tumours display sensitivity to small-molecule EGFR tyrosine kinase inhibitors (TKIs).

  • Prospective clinical trials have now validated the correlation between EGFR mutation and TKI sensitivity.

  • Multiple mechanisms of primary and secondary resistance of lung tumours to EGFR TKIs have been elucidated.

  • Unfortunately, all patients eventually develop acquired resistance. Secondary mutations in EGFR and/or amplification of the gene encoding the MET receptor tyrosine kinase account for most cases of resistance.

  • On the basis of promising preclinical data, many new rationally designed strategies are now being pursued in clinical trials to overcome acquired resistance.

  • EGFR-mutant lung cancer can serve as a model for other cancers driven by oncogenic kinases.

Abstract

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.

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Figure 1: Progress in the treatment of metastatic lung cancer.
Figure 2: Tissue accrual across multiple trials.
Figure 3: Comparison of TKI-sensitive and TKI-resistant mutations in cancer-derived mutant TKs.
Figure 4: Multi-pathway inhibition as a strategy to treat EGFR-mutant NSCLC.
Figure 5: Comparison of second-site mutation frequency following development of acquired resistance to TKI therapy.
Figure 6: Potential treatment strategies to cure EGFR-mutant lung cancer.

References

  1. Jemal, A. et al. Cancer statistics, 2009. CA Cancer J. Clin. 59, 225–249 (2009).

    PubMed  Article  Google Scholar 

  2. Goldstraw, P. et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J. Thorac. Oncol. 2, 706–714 (2007).

    PubMed  Article  Google Scholar 

  3. Hansen, H. H. et al. Combination chemotherapy of advanced lung cancer: a randomized trial. Cancer 38, 2201–2207 (1976).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  6. Marks, J. L. et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J. Thorac. Oncol. 3, 111–116 (2008).

    PubMed  Article  Google Scholar 

  7. Herbst, R. S. et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a Phase I trial. J. Clin. Oncol. 20, 3815–3825 (2002).

    CAS  PubMed  Article  Google Scholar 

  8. Albanell, J. et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J. Clin. Oncol. 20, 110–124 (2002).

    CAS  PubMed  Article  Google Scholar 

  9. Ranson, M. et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J. Clin. Oncol. 20, 2240–2250 (2002).

    CAS  PubMed  Article  Google Scholar 

  10. Nakagawa, K. et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors. Ann. Oncol. 14, 922–930 (2003).

    CAS  PubMed  Article  Google Scholar 

  11. 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).

    CAS  Article  PubMed  Google Scholar 

  12. 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). J. Clin. Oncol. 21, 2237–2246 (2003).

    CAS  PubMed  Article  Google Scholar 

  13. Miller, V. A. et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J. Clin. Oncol. 22, 1103–1109 (2004).

    CAS  PubMed  Article  Google Scholar 

  14. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  16. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. Nguyen, K. S., Kobayashi, S. & Costa, D. B. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin. Lung Cancer 10, 281–289 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  19. 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).

    CAS  PubMed  Article  Google Scholar 

  20. Mok, T. S. et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009). This paper presents results from IPASS (a randomized prospective Phase III clinical trial), which demonstrated the superiority of gefitinib over chemotherapy for the treatment of East Asian patients with chemotherapy-naive metastatic pulmonary adenocarcinoma harbouring EGFR mutations.

    CAS  PubMed  Article  Google Scholar 

  21. 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 (2009). This paper presents results from the WJTOG3405 trial (a randomized prospective Phase III clinical trial), which demonstrated the superiority of gefitinib over chemotherapy in prospectively genotyped Japanese patients with EGFR -mutant NSCLC.

    PubMed  Article  CAS  Google Scholar 

  22. Miller, V. A. et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J. Clin. Oncol. 26, 1472–1478 (2008).

  23. Rosell, R. et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361, 958–967 (2009). This paper shows the effectiveness of erlotinib in Caucasian (Spanish) patients with EGFR -mutant NSCLC.

    CAS  PubMed  Article  Google Scholar 

  24. Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010). References 20–24 definitively establish the clinical role of EGFR mutations and EGFR TKIs in lung cancer.

    CAS  PubMed  Article  Google Scholar 

  25. Yang, C. H. et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J. Clin. Oncol. 26, 2745–2753 (2008).

    CAS  PubMed  Article  Google Scholar 

  26. Han, S. W. et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J. Clin. Oncol. 23, 2493–2501 (2005).

    CAS  PubMed  Article  Google Scholar 

  27. Pao, W. & Ladanyi, M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin. Cancer Res. 13, 4954–4955 (2007).

    CAS  PubMed  Article  Google Scholar 

  28. Han, S. W. et al. Mucoepidermoid carcinoma of lung: potential target of EGFR-directed treatment. Lung Cancer 61, 30–34 (2008).

    PubMed  Article  Google Scholar 

  29. O'Neill, I. D. Gefitinib as targeted therapy for mucoepidermoid carcinoma of the lung: possible significance of CRTC1MAML2 oncogene. Lung Cancer 64, 129–130 (2009).

    PubMed  Article  Google Scholar 

  30. Coxon, A. et al. Mect1Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes. Cancer Res. 65, 7137–7144 (2005).

    CAS  PubMed  Article  Google Scholar 

  31. Behboudi, A. et al. Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1–MAML2 fusion oncogene. Genes Chromosomes Cancer 45, 470–481 (2006).

    CAS  PubMed  Article  Google Scholar 

  32. Hirsch, F. R. et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J. Clin. Oncol. 23, 6838–6845 (2005).

    CAS  PubMed  Article  Google Scholar 

  33. Cappuzzo, F. et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J. Natl Cancer Inst. 97, 643–655 (2005).

    CAS  PubMed  Article  Google Scholar 

  34. Hirsch, F. R. et al. Molecular predictors of outcome with gefitinib in a Phase III placebo-controlled study in advanced non-small-cell lung cancer. J. Clin. Oncol. 24, 5034–5042 (2006).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  36. Hirsch, F. R. et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann. Oncol. 18, 752–760 (2007).

    CAS  PubMed  Article  Google Scholar 

  37. Parra, H. S. et al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br. J. Cancer 91, 208–212 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Yeo, W.-L. et al. Erlotinib at a dose of 25 mg daily for non-small-cell lung cancers with EGFR mutations. J. Thorac. Oncol. 5, 1048–1053 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  39. Gandhi, J. et al. Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS ONE 4, e4576 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 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). This work confirms MET amplification as a mechanism of acquired resistance to gefitinib, extends the finding to erlotinib and shows that resistance can occur with or without the T790M change.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007). This paper reports the discovery of MET amplification as a mechanism of acquired resistance to gefitinib in cell line models and patient samples in mediating resistance. References 40 and 41 establish MET amplification as a mechanism of acquired resistance to EGFR TKIs in lung cancer.

    CAS  Article  PubMed  Google Scholar 

  42. Rosell, R., Viteri, S., Molina, M. A., Benlloch, S. & Taron, M. Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall-cell lung cancer. Curr. Opin. Oncol. 22, 112–120 (2010).

    CAS  PubMed  Article  Google Scholar 

  43. Mendelsohn, J. & Baselga, J. Epidermal growth factor receptor targeting in cancer. Semin. Oncol. 33, 369–385 (2006).

    CAS  Article  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  46. Hanna, N. et al. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J. Clin. Oncol. 24, 5253–5258 (2006).

    CAS  PubMed  Article  Google Scholar 

  47. 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).

    CAS  PubMed  Article  Google Scholar 

  48. Pirker, R. & Minar, W. Chemotherapy of advanced non-small cell lung cancer. Front. Radiat. Ther. Oncol. 42, 157–163 (2010).

    PubMed  Article  Google Scholar 

  49. 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).

    CAS  PubMed  Article  Google Scholar 

  50. 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).

    CAS  PubMed  Article  Google Scholar 

  51. Khambata-Ford, S. et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 918–927 (2010).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  53. Ji, H. et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9, 485–495 (2006).

    CAS  PubMed  Article  Google Scholar 

  54. 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). This paper identifies a potential new strategy to overcome T790M-mediated resistance using a small-molecule inhibitor (BIBW2992) combined with an EGFR-specific antibody (cetuximab) in an EGFR-L858R and T790M transgenic mouse model.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Soh, J. et al. Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS ONE 4, e7464 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. Balak, M. N. et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin. Cancer Res. 12, 6494–6501 (2006).

    CAS  PubMed  Article  Google Scholar 

  57. Weir, B. A. et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 450, 893–898 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Chitale, D. et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 28, 2773–2783 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 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). This paper proposes that the T790M mutation in EGFR causes drug resistance by restoring the affinity for ATP.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. Carey, K. D. et al. Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res. 66, 8163–8171 (2006).

    CAS  PubMed  Article  Google Scholar 

  63. Red Brewer, M. et al. The juxtamembrane region of the EGF receptor functions as an activation domain. Mol. Cell 34, 641–651 (2009).

    PubMed  Article  CAS  Google Scholar 

  64. Godin-Heymann, N. et al. Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer Res. 67, 7319–7326 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Mulloy, R. et al. Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib. Cancer Res. 67, 2325–2330 (2007).

    CAS  PubMed  Article  Google Scholar 

  66. Gong, Y. et al. Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med. 4, e294 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. Costa, D. B. et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin. Cancer Res. 14, 7060–7067 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Cragg, M. S., Kuroda, J., Puthalakath, H., Huang, D. C. & Strasser, A. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med. 4, 1681–1690 (2007).

    CAS  PubMed  Article  Google Scholar 

  69. Deng, J. et al. Proapoptotic BH3-only BCL-2 family prote in BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion. Cancer Res. 67, 11867–11875 (2007). References 66–69 show that the pro-apoptotic BCL-2 family member BIM is required for EGFR TKI-induced apoptosis in EGFR -mutant lung cancer and that the BCL-2 antagonist ABT-737 can enhance TKI-induced cell killing.

    CAS  PubMed  Article  Google Scholar 

  70. Faber, A. C., Wong, K. K. & Engelman, J. A. Differences underlying EGFR and HER2 oncogene addiction. Cell Cycle 9, 851–852 (2010).

    CAS  PubMed  Article  Google Scholar 

  71. Shigematsu, H. et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J. Natl Cancer Inst. 97, 339–346 (2005).

    CAS  PubMed  Article  Google Scholar 

  72. Politi, K. et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 20, 1496–1510 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Kosaka, T., Yatabe, Y., Onozato, R., Kuwano, H. & Mitsudomi, T. Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J. Thorac. Oncol. 4, 22–29 (2009).

    PubMed  Article  Google Scholar 

  74. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    CAS  PubMed  Article  Google Scholar 

  75. Wu, J. Y. et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin. Cancer Res. 14, 4877–4882 (2008).

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 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).

    CAS  PubMed  Article  Google Scholar 

  79. Prudkin, L., Tang, X. & Wistuba, I. I. Germ-line and somatic presentations of the EGFR T790M mutation in lung cancer. J. Thorac. Oncol. 4, 139–141 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  80. Tam, I. Y. et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin. Cancer Res. 12, 1647–1653 (2006).

    CAS  PubMed  Article  Google Scholar 

  81. Tam, I. Y. et al. Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations. Mol. Cancer Ther. 8, 2142–2151 (2009).

    CAS  PubMed  Article  Google Scholar 

  82. Kawano, O. et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 54, 209–215 (2006).

    PubMed  Article  Google Scholar 

  83. Engelman, J. A. et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J. Clin. Invest. 116, 2695–2706 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Vivanco, I. et al. The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation. Proc. Natl Acad. Sci. USA 107, 6459–6464 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Gong, Y. et al. High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS ONE 4, e7273 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 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).

    CAS  PubMed  Article  Google Scholar 

  90. Brose, M. S. et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997–7000 (2002).

    CAS  PubMed  Google Scholar 

  91. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    CAS  PubMed  Article  Google Scholar 

  92. Naoki, K., Chen, T. H., Richards, W. G., Sugarbaker, D. J. & Meyerson, M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 62, 7001–7003 (2002).

    CAS  PubMed  Google Scholar 

  93. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427–430 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Solit, D. B. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 (2006).

    CAS  PubMed  Article  Google Scholar 

  95. Pratilas, C. A. et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 68, 9375–9383 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Haura, E. B. et al. A Phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin. Cancer Res. 16, 2450–2457 (2010).

    CAS  PubMed  Article  Google Scholar 

  97. Soda, M. et al. Identification of the transforming EML4ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).

    CAS  Article  PubMed  Google Scholar 

  98. Rikova, K. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131, 1190–1203 (2007).

    CAS  PubMed  Article  Google Scholar 

  99. Horn, L. & Pao, W. EML4–ALK: honing in on a new target in non-small-cell lung cancer. J. Clin. Oncol. 27, 4232–4235 (2009).

    CAS  PubMed  Article  Google Scholar 

  100. Shaw, A. T. et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4–ALK. J. Clin. Oncol. 27, 4247–4253 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 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).

    CAS  PubMed  Article  Google Scholar 

  102. Turke, A. B. et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 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 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. Tamborini, E. et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127, 294–299 (2004).

    CAS  PubMed  Article  Google Scholar 

  105. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  107. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. Clarke, J. L., Pao, W., Wu, N., Miller, V. A. & Lassman, A. B. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J. Neurooncol. 99, 283–286 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  109. Jackman, D. M. et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J. Clin. Oncol. 24, 4517–4520 (2006).

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  111. Girard, N. et al. Analysis of genetic variants in never-smokers with lung cancer facilitated by an internet-based blood collection protocol: a preliminary report. Clin. Cancer Res. 16, 755–763 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Vikis, H. et al. EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity. Cancer Res. 67, 4665–4670 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Sos, M. L. et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res. 70, 868–874 (2010).

    CAS  PubMed  Article  Google Scholar 

  114. Mok, T. S. Living with imperfection. J. Clin. Oncol. 28, 191–192 (2010).

    CAS  PubMed  Article  Google Scholar 

  115. 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).

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  117. Kurata, T. et al. Effect of re-treatment with gefitinib ('Iressa', ZD1839) after acquisition of resistance. Ann. Oncol. 15, 173–174 (2004).

    CAS  PubMed  Article  Google Scholar 

  118. Oh, I.-J. et al. in AACR–IASLC Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy (Coronado, California USA, 2010).

    Google Scholar 

  119. Yano, S. et al. Retreatment of lung adenocarcinoma patients with gefitinib who had experienced favorable results from their initial treatment with this selective epidermal growth factor receptor inhibitor: a report of three cases. Oncol. Res. 15, 107–111 (2005).

    PubMed  Article  Google Scholar 

  120. Costa, D. B., Schumer, S. T., Tenen, D. G. & Kobayashi, S. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J. Clin. Oncol. 26, 1182–1186 (2008).

    PubMed  Article  Google Scholar 

  121. Bean, J. et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin. Cancer Res. 14, 7519–7525 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Avizienyte, E., Ward, R. A. & Garner, A. P. Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations. Biochem. J. 415, 197–206 (2008).

    CAS  PubMed  Article  Google Scholar 

  123. Costa, D. B. et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 4, 1669–1680 (2007).

    CAS  PubMed  Article  Google Scholar 

  124. Kumar, A., Petri, E. T., Halmos, B. & Boggon, T. J. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J. Clin. Oncol. 26, 1742–1751 (2008).

    CAS  PubMed  Article  Google Scholar 

  125. Politi, K., Fan, P. D., Shen, R., Zakowski, M. & Varmus, H. Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma. Dis. Model. Mech. 3, 111–119 (2010).

    CAS  PubMed  Article  Google Scholar 

  126. Frederick, B. A. et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol. Cancer Ther. 6, 1683–1691 (2007).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  128. Barr, S. et al. Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clin. Exp. Metastasis 25, 685–693 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  129. 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 

  130. 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).

    CAS  PubMed  Article  Google Scholar 

  131. Morinaga, R. et al. Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer 58, 411–413 (2007).

    PubMed  Article  Google Scholar 

  132. Tatematsu, A. et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin. Cancer Res. 14, 6092–6096 (2008).

    CAS  PubMed  Article  Google Scholar 

  133. Janne, P. A. et al. Preliminary activity and safety results from a phase I clinical trial of PF-00299804, an irreversible pan-HER inhibitor, in patients (pts) with NSCLC. J. Clin. Oncol. Abstr. 8027 (2010).

  134. Dziadziuszko, R., Camidge, D. R. & Hirsch, F. R. The insulin-like growth factor pathway in lung cancer. J. Thorac. Oncol. 3, 815–818 (2008).

    PubMed  Article  Google Scholar 

  135. Pao, G. & Girard, N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. (in the press)

  136. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. Carter, T. A. et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc. Natl Acad. Sci. USA 102, 11011–11016 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Sharma, S. V., Bell, D. W., Settleman, J. & Haber, D. A. Epidermal growth factor receptor mutations in lung cancer. Nature Rev. Cancer 7, 169–181 (2007).

    CAS  Article  Google Scholar 

  139. Wong, K. K. et al. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin. Cancer Res. 15, 2552–2558 (2009).

    CAS  PubMed  Article  Google Scholar 

  140. Sequist, L. V. et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a Phase II trial in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 3076–3083 (2010).

    CAS  PubMed  Article  Google Scholar 

  141. Li, D. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702–4711 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Engelman, J. A. et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 67, 11924–11932 (2007).

    CAS  PubMed  Article  Google Scholar 

  143. Gonzales, A. J. et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol. Cancer Ther. 7, 1880–1889 (2008).

    CAS  PubMed  Article  Google Scholar 

  144. Ogino, A. et al. Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line. Cancer Res. 67, 7807–7814 (2007).

    CAS  PubMed  Article  Google Scholar 

  145. 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). This paper shows that despite being more potent than gefitinib, the irreversible EGFR inhibitor HKI-272 actually selects for T790M-mediated resistance in vitro , suggesting that this class of compounds may not be as effective as hoped unless high concentrations can be achieved in patients.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Zhou, W. et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462, 1070–1074 (2009). This work reports the identification and characterization of WZ4002, a novel EGFR inhibitor with potent activity against EGFR-T790M-harbouring receptors.

  148. Li, D. et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12, 81–93 (2007).

    CAS  PubMed  Article  Google Scholar 

  149. Comoglio, P. M., Giordano, S. & Trusolino, L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature Rev. Drug Discov. 7, 504–516 (2008).

    CAS  Article  Google Scholar 

  150. Foo, J. & Michor, F. Evolution of resistance to targeted anti-cancer therapies during continuous and pulsed administration strategies. PLoS Comput. Biol. 5, e1000557 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Shah, N. P. et al. Potent, transient inhibition of BCR–ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 95, 232–240 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Schiller, J. H. et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 346, 92–98 (2002).

    CAS  PubMed  Article  Google Scholar 

  153. Sandler, A. et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).

    CAS  PubMed  Article  Google Scholar 

  154. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  156. Eberhard, D. A. et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23, 5900–5909 (2005).

    CAS  PubMed  Article  Google Scholar 

  157. Kim, E. S. et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised Phase III trial. Lancet 372, 1809–1818 (2008).

    CAS  PubMed  Article  Google Scholar 

  158. 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).

    CAS  PubMed  Article  Google Scholar 

  159. Zhu, C. Q. et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J. Clin. Oncol. 26, 4268–4275 (2008).

    CAS  PubMed  Article  Google Scholar 

  160. Bell, D. W. et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J. Clin. Oncol. 23, 8081–8092 (2005).

    CAS  PubMed  Article  Google Scholar 

  161. Shah, N. P. et al. Multiple BCR–ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117–125 (2002).

    CAS  PubMed  Article  Google Scholar 

  162. Branford, S. et al. Detection of BCR–ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102, 276–283 (2003).

    CAS  PubMed  Article  Google Scholar 

  163. Antonescu, C. R. et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin. Cancer Res. 11, 4182–4190 (2005).

    CAS  PubMed  Article  Google Scholar 

  164. Wardelmann, E. et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin. Cancer Res. 12, 1743–1749 (2006).

    CAS  PubMed  Article  Google Scholar 

  165. Cowan-Jacob, S. W. et al. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr. D Biol. Crystallogr. 63, 80–93 (2007).

    CAS  PubMed  Article  Google Scholar 

  166. Mol., C. D. et al. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J. Biol. Chem. 279, 31655–31663 (2004).

    CAS  PubMed  Article  Google Scholar 

  167. Pettersen, E. F. et al. UCSF Chimera — a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    CAS  PubMed  Article  Google Scholar 

  168. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  170. 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).

    CAS  PubMed  Article  Google Scholar 

  171. 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).

    CAS  PubMed  Article  Google Scholar 

  172. Wakeling, A. E. et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 62, 5749–5754 (2002).

    CAS  PubMed  Google Scholar 

  173. Hidalgo, M. et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J. Clin. Oncol. 19, 3267–3279 (2001).

    CAS  PubMed  Article  Google Scholar 

  174. Gendreau, S. B. et al. Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin. Cancer Res. 13, 3713–3723 (2007).

    CAS  PubMed  Article  Google Scholar 

  175. Ryan, A. J. & Wedge, S. R. ZD6474 — a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br. J. Cancer 92 (Suppl. 1), 6–13 (2005).

    Article  CAS  Google Scholar 

  176. Xia, W. et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21, 6255–6263 (2002).

    CAS  Article  PubMed  Google Scholar 

  177. Erlichman, C. et al. Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J. Clin. Oncol. 24, 2252–2260 (2006).

    CAS  PubMed  Article  Google Scholar 

  178. Rabindran, S. K. et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 64, 3958–3965 (2004).

    CAS  PubMed  Article  Google Scholar 

  179. Allen, L. F., Eiseman, I. A., Fry, D. W. & Lenehan, P. F. CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer. Semin. Oncol. 30, 65–78 (2003).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

The authors would like to apologize to those whose work was not included owing to space constraints. They thank C. Lovly, K. Politi and M. R. Brewer for their insightful feedback on the manuscript, and M. R. Brewer for assistance with the crystal structure diagrams. This work was supported by US National Institutes of Health (NIH) National Cancer Institute (NCI) grants R01-CA121210, P01-CA129243 and U54-CA143798. W.P. received additional support from Vanderbilt's Specialized Program of Research Excellence in Lung Cancer grant (CA90949) and the Vanderbilt-Ingram Cancer Center (VICC) core grant (P30-CA68485).

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Rights to EGFR T790M testing were licensed on behalf of William Pao and others to Molecular MD. William Pao has received research funding from Exelixis and has consulted for Molecular MD, AstraZeneca, Bristol-Myers Squibb and Symphony Evolution.

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DATABASES

National Cancer Institute Drug Dictionary

bevacizumab

BIBW2992

carboplatin–paclitaxel

cetuximab

cisplatin

dasatinib

docetaxel

erlotinib

gefitinib

imatinib

neratinib

panitumumab

PD0325901

PF-00299804

rapamycin

RCSB Data Bank

ABL

EGFR

KIT

FURTHER INFORMATION

William Pao's homepage

USCF Chimera molecular modelling tool

Glossary

Driver mutation

An oncogenic mutation that induces and sustains tumorigenesis.

Oncogene addiction

The phenomenon in which cancer cells become dependent on or addicted to signalling from oncogenic mutants for survival.

Primary resistance

The initial resistance to therapy.

Gefitinib

The first quinazoline-based reversible small-molecule EGFR tyrosine kinase inhibitor.

Erlotinib

An FDA-approved quinazoline-based EGFR inhibitor.

Prospective single-arm study

A clinical trial in which a drug is administered in a prospective manner to a single group of patients (defined by certain characteristics) to see whether their condition improves. Single-arm studies are distinct from two-arm studies, in which a group of patients is randomly administered one of two possible treatments (for example, an experimental treatment versus standard treatment) to determine which treatment is better.

Response rate

RR. The proportion of patients undergoing a documented radiographic response as determined by response evaluation criteria in solid tumours.

Progression-free survival

PFS. The length of time during and after treatment in which a disease does not progress.

Time to progression

TTP. Time from the beginning of treatment until treatment failure.

Never smoker

An individual who has smoked <100 cigarettes in their lifetime.

Former light smoker

An individual who has stopped smoking for at least 15 years previously and has a total of ≤10 pack-years of smoking.

Carboplatin–paclitaxel

An example of a platinum doublet for first-line treatment of NSCLC.

Hazard ratio

HR. A measure of how often an event happens in one group compared with how often it happens in another group.

Confidence interval

CI. A calculated value that shows the range in which a particular treatment effect is likely to be observed.

Chimeric IgG monoclonal antibody

A recombinant antibody made from two species (in the case of cetuximab, the fusion contains human and mouse sequences).

Acquired resistance

Resistance that develops after the initial response to therapy.

Gatekeeper residue

A conserved residue that lies at the opening of the ATP-binding pocket in several kinases.

Disease flare

Rapid tumour growth following withdrawal of therapy.

Resistance mutation screen

A comprehensive cell-based screen to identify all potential mutations in a target gene that confer resistance to a given agent.

Irreversible EGFR inhibitor

A small-molecule inhibitor that binds permanently in the ATP-binding pocket of EGFR through a covalent bond at C797.

Chemogenomic profiling

The technique of coupling chemical compound sensitivity to genomic signatures.

Quinazoline core

A scaffold built on the fusion of a benzene ring and a pyrimidine ring.

Anilinopyrimidine core

A scaffold built on an anilino group and pyrimidine ring.

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Pao, W., Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10, 760–774 (2010). https://doi.org/10.1038/nrc2947

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