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

Nature Reviews Cancer

Volumn 10, Issue 11, 2010, Pages 760-774

  Pao, William ^a   Chmielecki, Juliann ^b  

^a VANDERBILT INGRAM CANCER CENTER   (United States)

^b Weill Cornell Medical Center   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [1 (2,6 DICHLORO 3 FLUOROPHENYL)ETHOXY] 5 [1 (4 PIPERIDINYL) 1H PYRAZOL 4 YL] 2 PYRIDINYLAMINE; 4 [3 CHLORO 4 (2 PYRIDINYLMETHOXY)ANILINO] 3 CYANO 6 (4 DIMETHYLAMINOCROTONAMIDO) 7 ETHOXYQUINOLINE; ANTINEOPLASTIC AGENT; ARQ 197; CANERTINIB; CETUXIMAB; DASATINIB; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; GEFITINIB; GSK 2118436; IMATINIB; JNJ 38877605; LAPATINIB; N [4 (3 CHLORO 4 FLUOROANILINO) 7 (TETRAHYDRO 3 FURYLOXY) 6 QUINAZOLINYL] 4 DIMETHYLAMINO 2 BUTENAMIDE; OSI 906; PANITUMUMAB; PELITINIB; PF 299804; PLACEBO; PLX 4032; PROTEIN TYROSINE KINASE INHIBITOR; RAPAMYCIN; SCH 900105; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; WZ 4002; XL 184; XL 647; XL 880;

ANTINEOPLASTIC ACTIVITY; CANCER INHIBITION; CANCER RESISTANCE; CLINICAL TRIAL; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG MECHANISM; GENE MUTATION; HUMAN; IN VITRO STUDY; LUNG NON SMALL CELL CANCER; NONHUMAN; PRIORITY JOURNAL; REVIEW; TREATMENT RESPONSE;

ANTINEOPLASTIC AGENTS; CARCINOMA, NON-SMALL-CELL LUNG; DRUG RESISTANCE, NEOPLASM; HUMANS; LUNG NEOPLASMS; MUTATION; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; RECEPTOR, EPIDERMAL GROWTH FACTOR;

EID: 77958478674     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc2947     Document Type: Review

References (179)

1. Jemal, A. et al. Cancer statistics, 2009. CA CancerJ. Clin. 59, 225-249 (2009).
2. Goldstraw, P. et al. The IASLC Lung Cancer StagingProject: proposals for the revision of the TNM stagegroupings in the forthcoming (seventh) edition of theTNM classification of malignant tumours. J. Thorac. Oncol. 2, 706-714 (2007).
3. Hansen, H. H. et al. Combination chemotherapy ofadvanced lung cancer: a randomized trial. Cancer 38,2201-2207 (1976).
4. Weinstein, I. B. Cancer. Addiction to oncogenes theAchilles heal of cancer. Science 297, 63-64 (2002).
5. Hynes, N. E. & Lane, H. A. ERBB receptors and cancer:the complexity of targeted inhibitors. Nature Rev. Cancer 5, 341-354 (2005).
6. Marks, J. L. et al. Prognostic and therapeuticimplications of EGFR and KRAS mutations in resectedlung adenocarcinoma. J. Thorac. Oncol. 3, 111-116(2008).
7. Herbst, R. S. et al. Selective oral epidermal growthfactor receptor tyrosine kinase inhibitor ZD1839 isgenerally well-tolerated and has activity innon-small-cell lung cancer and other solid tumors:results of a Phase I trial. J. Clin. Oncol. 20,3815-3825 (2002).
8. Albanell, J. et al. Pharmacodynamic studies of theepidermal growth factor receptor inhibitor ZD1839 inskin from cancer patients: histopathologic andmolecular consequences of receptor inhibition. J. Clin. Oncol. 20, 110-124 (2002).
9. Ranson, M. et al. ZD1839, a selective oral epidermalgrowth factor receptor-tyrosine kinase inhibitor, is welltolerated and active in patients with solid, malignanttumors: results of a phase I trial. J. Clin. Oncol. 20,2240-2250 (2002).
10. Nakagawa, K. et al. Phase I pharmacokinetic trial ofthe selective oral epidermal growth factor receptortyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) inJapanese patients with solid malignant tumors. Ann. Oncol. 14, 922-930 (2003).
11. Kris, M. G. et al. Efficacy of gefitinib, an inhibitor ofthe epidermal growth factor receptor tyrosine kinase,in symptomatic patients with non-small cell lungcancer: a randomized trial. JAMA 290, 2149-2158(2003).
12. Fukuoka, M. et al. Multi-institutional randomizedPhase II trial of gefitinib for previously treatedpatients with advanced non-small-cell lung cancer(The IDEAL 1 Trial). J. Clin. Oncol. 21, 2237-2246(2003).
13. Miller, V. A. et al. Bronchioloalveolar pathologicsubtype and smoking history predict sensitivity togefitinib in advanced non-small-cell lung cancer. J. Clin. Oncol. 22, 1103-1109 (2004).
14. Lynch, T. J. et al. Activating mutations in the epidermalgrowth factor receptor underlying responsiveness ofnon-small-cell lung cancer to gefitinib. N. Engl. J. Med.350, 2129-2139 (2004).
15. Paez, J. G. et al. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science 304, 1497-1500 (2004).
16. Pao, W. et al. EGF receptor gene mutations arecommon in lung cancers from 'never smokers' and areassociated with sensitivity of tumors to gefitinib anderlotinib. Proc. Natl Acad. Sci. USA 101, 13306-13311 (2004).
17. Nguyen, K. S., Kobayashi, S. & Costa, D. B. Acquiredresistance to epidermal growth factor receptortyrosine kinase inhibitors in non-small-cell lungcancers dependent on the epidermal growth factorreceptor pathway. Clin. Lung Cancer 10, 281-289(2009).
18. Shepherd, F. A. et al. Erlotinib in previously treatednon-small-cell lung cancer. N. Engl. J. Med. 353,123-132 (2005).
19. Thatcher, N. et al. Gefitinib plus best supportive carein previously treated patients with refractory advancednon-small-cell lung cancer: results from a randomised,placebo-controlled, multicentre study (Iressa SurvivalEvaluation in Lung Cancer). Lancet 366, 1527-1537(2005).
20. Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel inpulmonary adenocarcinoma. N. Engl. J. Med. 361,947-957 (2009).
21. Mitsudomi, T. et al. Gefitinib versus cisplatin plusdocetaxel in patients with non-small-cell lung cancerharbouring mutations of the epidermal growthfactor receptor (WJTOG3405): an open label,randomised Phase 3 trial. Lancet Oncol. 11,121-128 (2009).
22. Miller, V. A. et al. Molecular characteristics ofbronchioloalveolar carcinoma and adenocarcinoma,bronchioloalveolar carcinoma subtype, predictresponse to erlotinib. J. Clin. Oncol. 26, 1472-1478(2008).
23. Rosell, R. et al. Screening for epidermal growth factorreceptor mutations in lung cancer. N. Engl. J. Med.361, 958-967 (2009).
24. Maemondo, M. et al. Gefitinib or chemotherapy fornon-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380-2388 (2010).
25. Yang, C. H. et al. Specific EGFR mutations predicttreatment outcome of stage IIIB/IV patients withchemotherapy-naive non-small-cell lung cancerreceiving first-line gefitinib monotherapy. J. Clin. Oncol. 26, 2745-2753 (2008).
26. Han, S. W. et al. Predictive and prognostic impact ofepidermal growth factor receptor mutation innon-small-cell lung cancer patients treated withgefitinib. J. Clin. Oncol. 23, 2493-2501 (2005).
27. Pao, W. & Ladanyi, M. Epidermal growth factorreceptor mutation testing in lung cancer: searching forthe ideal method. Clin. Cancer Res. 13, 4954-4955(2007).
28. Han, S. W. et al. Mucoepidermoid carcinoma of lung:potential target of EGFR-directed treatment. LungCancer 61, 30-34 (2008).
29. O'Neill, I. D. Gefitinib as targeted therapy formucoepidermoid carcinoma of the lung: possiblesignificance of CRTC1-MAML2 oncogene. LungCancer 64, 129-130 (2009).
30. Coxon, A. et al. Mect1-Maml2 fusion oncogenelinked to the aberrant activation of cyclic AMP/CREBregulated genes. Cancer Res. 65, 7137-7144(2005).
31. Behboudi, A. et al. Molecular classification ofmucoepidermoid carcinomas-prognostic significanceof the MECT1-MAML2 fusion oncogene. GenesChromosomes Cancer 45, 470-481 (2006).
32. Hirsch, F. R. et al. Increased epidermal growth factorreceptor gene copy number detected by fluorescencein situ hybridization associates with increasedsensitivity to gefitinib in patients withbronchioloalveolar carcinoma subtypes: a SouthwestOncology Group Study. J. Clin. Oncol. 23,6838-6845 (2005).
33. Cappuzzo, F. et al. Epidermal growth factor receptorgene and protein and gefitinib sensitivity innon-small-cell lung cancer. J. Natl Cancer Inst. 97,643-655 (2005).
34. Hirsch, F. R. et al. Molecular predictors of outcomewith gefitinib in a Phase III placebo-controlled study inadvanced non-small-cell lung cancer. J. Clin. Oncol.24, 5034-5042 (2006).
35. Tsao, M. S. et al. Erlotinib in lung cancer \-molecularand clinical predictors of outcome. N. Engl. J. Med.353, 133-144 (2005).
36. Hirsch, F. R. et al. Combination of EGFR gene copynumber and protein expression predicts outcomefor advanced non-small-cell lung cancer patientstreated with gefitinib. Ann. Oncol. 18, 752-760(2007).
37. Parra, H. S. et al. Analysis of epidermal growth factorreceptor expression as a predictive factor for responseto gefitinib ('Iressa', ZD1839) in non-small-cell lungcancer. Br. J. Cancer 91, 208-212 (2004).
38. Yeo, W.-L. et al. Erlotinib at a dose of 25 mg daily fornon-small-cell lung cancers with EGFR mutations. J. Thorac. Oncol. 5, 1048-1053 (2010).
39. Gandhi, J. et al. Alterations in genes of the EGFRsignaling pathway and their relationship to EGFRtyrosine kinase inhibitor sensitivity in lung cancer celllines. PLoS ONE 4, e4576 (2009).
40. Bean, J. et al. MET amplification occurs with orwithout T790M mutations in EGFR mutant lungtumors with acquired resistance to gefitinib orerlotinib. Proc. Natl Acad. Sci. USA 104,20932-20937 (2007).
41. Engelman, J. A. et al. MET amplification leads togefitinib resistance in lung cancer by activating ERBB3signaling. Science 316, 1039-1043 (2007).
42. Rosell, R., Viteri, S., Molina, M. A., Benlloch, S. & Taron, M. Epidermal growth factor receptor tyrosinekinase inhibitors as first-line treatment in advancednonsmall-cell lung cancer. Curr. Opin. Oncol. 22,112-120 (2010).
43. Mendelsohn, J. & Baselga, J. Epidermal growth factorreceptor targeting in cancer. Semin. Oncol. 33,369-385 (2006).
44. Bonner, J. A. et al. Radiotherapy plus cetuximab forsquamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354, 567-578 (2006).
45. Jonker, D. J. et al. Cetuximab for the treatment ofcolorectal cancer. N. Engl. J. Med. 357, 2040-2048(2007).
46. Hanna, N. et al. Phase II trial of cetuximab in patientswith previously treated non-small-cell lung cancer. J. Clin. Oncol. 24, 5253-5258 (2006).
47. Rosell, R. et al. Randomized Phase II study ofcetuximab plus cisplatin/vinorelbine compared withcisplatin/vinorelbine alone as first-line therapy inEGFR-expressing advanced non-small-cell lung cancer. Ann. Oncol. 19, 362-369 (2008).
48. Pirker, R. & Minar, W. Chemotherapy of advanced nonsmallcell lung cancer. Front. Radiat. Ther. Oncol. 42,157-163 (2010).
49. Lynch, T. J. et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-celllung cancer: results of the randomized multicenterPhase III trial BMS099. J. Clin. Oncol. 28, 911-917(2010).
50. Mukohara, T. et al. Differential effects of gefitinib andcetuximab on non-small-cell lung cancers bearingepidermal growth factor receptor mutations. J. NatlCancer Inst. 97, 1185-1194 (2005).
51. Khambata-Ford, S. et al. Analysis of potentialpredictive 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).
52. Li, S. et al. Structural basis for inhibition of theepidermal growth factor receptor by cetuximab. Cancer Cell 7, 301-311 (2005).
53. Ji, H. et al. The impact of human EGFR kinase domainmutations on lung tumorigenesis and in vivo sensitivityto EGFR-targeted therapies. Cancer Cell 9, 485-495(2006).
54. Regales, L. et al. Dual targeting of EGFR can overcomea major drug resistance mutation in mouse models ofEGFR mutant lung cancer. J. Clin. Invest. 119,3000-3010 (2009).
55. Soh, J. et al. Oncogene mutations, copy number gainsand mutant allele specific imbalance (MASI) frequentlyoccur together in tumor cells. PLoS ONE 4, e7464(2009).
56. Balak, M. N. et al. Novel D761Y and commonsecondary T790M mutations in epidermal growthfactor receptor-mutant lung adenocarcinomas withacquired resistance to kinase inhibitors. Clin. CancerRes. 12, 6494-6501 (2006).
57. Weir, B. A. et al. Characterizing the cancer genome inlung adenocarcinoma. Nature 450, 893-898(2007).
58. Ding, L. et al. Somatic mutations affect key pathwaysin lung adenocarcinoma. Nature 455, 1069-1075(2008).
59. Chitale, D. et al. An integrated genomic analysis oflung cancer reveals loss of DUSP4 in EGFR-mutanttumors. Oncogene 28, 2773-2783 (2009).
60. Yun, C. H. et al. Structures of lung cancer-derivedEGFR mutants and inhibitor complexes: mechanism ofactivation and insights into differential inhibitorsensitivity. Cancer Cell 11, 217-227 (2007).
61. Yun, C. H. et al. The T790M mutation in EGFR kinasecauses drug resistance by increasing the affinity forATP. Proc. Natl Acad. Sci. USA 105, 2070-2075(2008).
62. Carey, K. D. et al. Kinetic analysis of epidermal growthfactor receptor somatic mutant proteins showsincreased sensitivity to the epidermal growth factorreceptor tyrosine kinase inhibitor, erlotinib. CancerRes. 66, 8163-8171 (2006).
63. Red Brewer, M. et al. The juxtamembrane region ofthe EGF receptor functions as an activation domain. Mol. Cell 34, 641-651 (2009).
64. Godin-Heymann, N. et al. Oncogenic activity ofepidermal growth factor receptor kinase mutantalleles is enhanced by the T790M drug resistancemutation. Cancer Res. 67, 7319-7326 (2007).
65. Mulloy, R. et al. Epidermal growth factor receptormutants from human lung cancers exhibit enhancedcatalytic activity and increased sensitivity to gefitinib. Cancer Res. 67, 2325-2330 (2007).
66. Gong, Y. et al. Induction of BIM is essential forapoptosis triggered by EGFR kinase inhibitors inmutant EGFR-dependent lung adenocarcinomas. PLoSMed. 4, e294 (2007).
67. Costa, D. B. et al. Effects of erlotinib in EGFR mutatednon-small cell lung cancers with resistance to gefitinib. Clin. Cancer Res. 14, 7060-7067 (2008).
68. Cragg, M. S., Kuroda, J., Puthalakath, H., Huang,D. C. & Strasser, A. Gefitinib-induced killing of NSCLCcell lines expressing mutant EGFR requires BIM andcan be enhanced by BH3 mimetics. PLoS Med. 4,1681-1690 (2007).
69. Deng, J. et al. Proapoptotic BH3-only BCL-2 familyprote in BIM connects death signaling fromepidermal growth factor receptor inhibition to themitochondrion. Cancer Res. 67, 11867-11875(2007).
70. Faber, A. C., Wong, K. K. & Engelman, J. A. Differencesunderlying EGFR and HER2 oncogene addiction. CellCycle 9, 851-852 (2010).
71. Shigematsu, H. et al. Clinical and biological featuresassociated with epidermal growth factor receptor genemutations in lung cancers. J. Natl Cancer Inst. 97,339-346 (2005).
72. Politi, K. et al. Lung adenocarcinomas induced in miceby mutant EGF receptors found in human lung cancersrespond to a tyrosine kinase inhibitor or to downregulationof the receptors. Genes Dev. 20,1496-1510 (2006).
73. Kosaka, T., Yatabe, Y., Onozato, R., Kuwano, H. & Mitsudomi, T. Prognostic implication of EGFR, KRAS,and TP53 gene mutations in a large cohort ofJapanese patients with surgically treated lungadenocarcinoma. J. Thorac. Oncol. 4, 22-29(2009).
74. Eisenhauer, E. A. et al. New response evaluationcriteria in solid tumours: revised RECIST guideline(version 1.1). Eur. J. Cancer 45, 228-247 (2009).
75. Wu, J. Y. et al. Lung cancer with epidermal growthfactor receptor exon 20 mutations is associated withpoor gefitinib treatment response. Clin. Cancer Res.14, 4877-4882 (2008).
76. Greulich, H. et al. Oncogenic transformation byinhibitor-sensitive and-resistant EGFR mutants. PLoSMed. 2, e313 (2005).
77. Maheswaran, S. et al. Detection of mutations in EGFRin circulating lung-cancer cells. N. Engl. J. Med. 359,366-377 (2008).
78. Inukai, M. et al. Presence of epidermal growth factorreceptor gene T790M mutation as a minor clone innon-small cell lung cancer. Cancer Res. 66,7854-7858 (2006).
79. Prudkin, L., Tang, X. & Wistuba, I. I. Germ-line andsomatic presentations of the EGFR T790M mutationin lung cancer. J. Thorac. Oncol. 4, 139-141(2009).
80. Tam, I. Y. et al. Distinct epidermal growth factorreceptor and KRAS mutation patterns in non-small celllung cancer patients with different tobacco exposureand clinicopathologic features. Clin. Cancer Res. 12,1647-1653 (2006).
81. Tam, I. Y. et al. Double EGFR mutants containing rareEGFR mutant types show reduced in vitro response togefitinib compared with common activating missensemutations. Mol. Cancer Ther. 8, 2142-2151 (2009).
82. Kawano, O. et al. PIK3CA mutation status in Japaneselung cancer patients. Lung Cancer 54, 209-215(2006).
83. Engelman, J. A. et al. Allelic dilution obscuresdetection of a biologically significant resistancemutation in EGFR-amplified lung cancer. J. Clin. Invest.116, 2695-2706 (2006).
84. Sos, M. L. et al. PTEN loss contributes to erlotinibresistance in EGFR-mutant lung cancer by activationof Akt and EGFR. Cancer Res. 69, 3256-3261(2009).
85. Vivanco, I. et al. The phosphatase and tensin homologregulates epidermal growth factor receptor (EGFR)inhibitor response by targeting EGFR for degradation. Proc. Natl Acad. Sci. USA 107, 6459-6464 (2010).
86. Sharma, S. V. et al. A chromatin-mediated reversibledrug-tolerant state in cancer cell subpopulations. Cell141, 69-80 (2010).
87. Gong, Y. et al. High expression levels of total IGF-1Rand sensitivity of NSCLC cells in vitro to an anti-IGF-1Rantibody (R1507). PLoS ONE 4, e7273 (2009).
88. Pao, W. et al. KRAS mutations and primary resistanceof lung adenocarcinomas to gefitinib or erlotinib. PLoSMed. 2, e17 (2005).
89. Linardou, H. et al. Assessment of somatic k?RASmutations as a mechanism associated with resistanceto EGFR-targeted agents: a systematic review andmeta-analysis of studies in advanced non-small-celllung cancer and metastatic colorectal cancer. LancetOncol. 9, 962-972 (2008).
90. Brose, M. S. et al. BRAF and RAS mutations in humanlung cancer and melanoma. Cancer Res. 62,6997-7000 (2002).
91. Davies, H. et al. Mutations of the BRAF gene in humancancer. Nature 417, 949-954 (2002).
92. Naoki, K., Chen, T. H., Richards, W. G., Sugarbaker,D. J. & Meyerson, M. Missense mutations of the BRAFgene in human lung adenocarcinoma. Cancer Res. 62,7001-7003 (2002).
93. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimersand ERK signalling in cells with wild-type BRAF. Nature464, 427-430 (2010).
94. Solit, D. B. et al. BRAF mutation predicts sensitivity toMEK inhibition. Nature 439, 358-362 (2006).
95. Pratilas, C. A. et al. Genetic predictors of MEKdependence in non-small cell lung cancer. Cancer Res.68, 9375-9383 (2008).
96. Haura, E. B. et al. A Phase II study of PD-0325901, anoral MEK inhibitor, in previously treated patients withadvanced non-small cell lung cancer. Clin. Cancer Res.16, 2450-2457 (2010).
97. Soda, M. et al. Identification of the transformingEML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566 (2007).
98. Rikova, K. et al. Global survey of phosphotyrosinesignaling identifies oncogenic kinases in lung cancer. Cell 131, 1190-1203 (2007).
99. Horn, L. & Pao, W. EML4-ALK: honing in on a newtarget in non-small-cell lung cancer. J. Clin. Oncol. 27,4232-4235 (2009).
100. Shaw, A. T. et al. Clinical features and outcome ofpatients with non-small-cell lung cancer who harborEML4-ALK. J. Clin. Oncol. 27, 4247-4253 (2009).
101. Yano, S. et al. Hepatocyte growth factor inducesgefitinib resistance of lung adenocarcinoma withepidermal growth factor receptor-activating mutations. Cancer Res. 68, 9479-9487 (2008).
102. Turke, A. B. et al. Preexistence and clonal selection ofMET amplification in EGFR mutant NSCLC. Cancer Cell17, 77-88 (2010).
103. Jackman, D. et al. Clinical definition of acquiredresistance to epidermal growth factor receptortyrosine kinase inhibitors in non-small-cell lung cancer. J. Clin. Oncol. 28, 357-360 (2009).
104. Tamborini, E. et al. A new mutation in the KIT ATPpocket causes acquired resistance to imatinib in agastrointestinal stromal tumor patient. Gastroenterology 127, 294-299 (2004).
105. Gorre, M. E. et al. Clinical resistance to STI-571 cancertherapy caused by BCR-ABL gene mutation oramplification. Science 293, 876-880 (2001).
106. Kobayashi, S. et al. EGFR mutation and resistance ofnon-small-cell lung cancer to gefitinib. N. Engl. J. Med.352, 786-792 (2005).
107. Pao, W. et al. Acquired resistance of lungadenocarcinomas to gefitinib or erlotinib is associatedwith a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).
108. Clarke, J. L., Pao, W., Wu, N., Miller, V. A. & Lassman,A. B. High dose weekly erlotinib achieves therapeuticconcentrations in CSF and is effective inleptomeningeal metastases from epidermal growthfactor receptor mutant lung cancer. J. Neurooncol. 99,283-286 (2010).
109. Jackman, D. M. et al. Response and resistance in anon-small-cell lung cancer patient with an epidermalgrowth factor receptor mutation and leptomeningealmetastases treated with high-dose gefitinib. J. Clin. Oncol. 24, 4517-4520 (2006).
110. Bell, D. W. et al. Inherited susceptibility to lung cancermay be associated with the T790M drug resistancemutation in EGFR. Nature Genet. 37, 1315-1316(2005).
111. Girard, N. et al. Analysis of genetic variants in neversmokerswith lung cancer facilitated by an internetbasedblood collection protocol: a preliminary report. Clin. Cancer Res. 16, 755-763 (2010).
112. Vikis, H. et al. EGFR-T790M is a rare lung cancersusceptibility allele with enhanced kinase activity. Cancer Res. 67, 4665-4670 (2007).
113. Sos, M. L. et al. Chemogenomic profiling providesinsights into the limited activity of irreversible EGFRinhibitors in tumor cells expressing the T790M EGFRresistance mutation. Cancer Res. 70, 868-874 (2010).
114. Mok, T. S. Living with imperfection. J. Clin. Oncol. 28,191-192 (2010).
115. Riely, G. J. et al. Prospective assessment ofdiscontinuation and reinitiation of erlotinib or gefitinibin patients with acquired resistance to erlotinib orgefitinib followed by the addition of everolimus. Clin. Cancer Res. 13, 5150-5155 (2007).
116. Milton, D. T. et al. Molecular on/off switch. J. Clin. Oncol. 24, 4940-4942 (2006).
117. Kurata, T. et al. Effect of re-treatment with gefitinib('Iressa', ZD1839) after acquisition of resistance. Ann. Oncol. 15, 173-174 (2004).
118. Oh, I.-J. et al. in AACR-IASLC Joint Conference onMolecular Origins of Lung Cancer: Prospects forPersonalized Prevention and Therapy (Coronado,California USA, 2010).
119. Yano, S. et al. Retreatment of lung adenocarcinomapatients with gefitinib who had experiencedfavorable results from their initial treatment withthis selective epidermal growth factor receptorinhibitor: a report of three cases. Oncol. Res. 15,107-111 (2005).
120. Costa, D. B., Schumer, S. T., Tenen, D. G. & Kobayashi,S. Differential responses to erlotinib in epidermalgrowth factor receptor (EGFR)-mutated lung cancerswith acquired resistance to gefitinib carrying theL747S or T790M secondary mutations. J. Clin. Oncol.26, 1182-1186 (2008).
121. Bean, J. et al. Acquired resistance to epidermal growthfactor receptor kinase inhibitors associated with anovel T854A mutation in a patient with EGFR-mutantlung adenocarcinoma. Clin. Cancer Res. 14,7519-7525 (2008).
122. Avizienyte, E., Ward, R. A. & Garner, A. P. Comparisonof the EGFR resistance mutation profiles generated byEGFR-targeted tyrosine kinase inhibitors and theimpact of drug combinations. Biochem. J. 415,197-206 (2008).
123. Costa, D. B. et al. BIM mediates EGFR tyrosine kinaseinhibitor-induced apoptosis in lung cancers withoncogenic EGFR mutations. PLoS Med. 4,1669-1680 (2007).
124. Kumar, A., Petri, E. T., Halmos, B. & Boggon, T. J. Structure and clinical relevance of the epidermalgrowth factor receptor in human cancer. J. Clin. Oncol.26, 1742-1751 (2008).
125. Politi, K., Fan, P. D., Shen, R., Zakowski, M. & Varmus,H. Erlotinib resistance in mouse models of epidermalgrowth factor receptor-induced lung adenocarcinoma. Dis. Model. Mech. 3, 111-119 (2010).
126. Frederick, B. A. et al. Epithelial to mesenchymaltransition predicts gefitinib resistance in cell lines ofhead and neck squamous cell carcinoma and nonsmallcell lung carcinoma. Mol. Cancer Ther. 6,1683-1691 (2007).
127. Uramoto, H. et al. Epithelial-mesenchymal transitionin EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res. 30, 2513-2517 (2010).
128. Barr, S. et al. Bypassing cellular EGF receptordependence through epithelial-to-mesenchymal-liketransitions. Clin. Exp. Metastasis 25, 685-693 (2008).
129. Guix, M. et al. Acquired resistance to EGFR tyrosinekinase inhibitors in cancer cells is mediated by loss ofIGF-binding proteins. J. Clin. Invest. 118, 2609-2619(2008).
130. Zakowski, M. F., Ladanyi, M. & Kris, M. G. EGFRmutations in small-cell lung cancers in patients whohave never smoked. N. Engl. J. Med. 355, 213-215(2006).
131. Morinaga, R. et al. Sequential occurrence of non-smallcell and small cell lung cancer with the same EGFRmutation. Lung Cancer 58, 411-413 (2007).
132. Tatematsu, A. et al. Epidermal growth factor receptormutations in small cell lung cancer. Clin. Cancer Res.14, 6092-6096 (2008).
133. Janne, P. A. et al. Preliminary activity and safetyresults from a phase I clinical trial of PF-00299804,an irreversible pan-HER inhibitor, in patients (pts) withNSCLC. J. Clin. Oncol. Abstr. 8027 (2010).
134. Dziadziuszko, R., Camidge, D. R. & Hirsch, F. R. Theinsulin-like growth factor pathway in lung cancer. J. Thorac. Oncol. 3, 815-818 (2008).
135. Pao, G. & Girard, N. New driver mutations in nonsmall-cell lung cancer. Lancet Oncol. (in the press)
136. Kwak, E. L. et al. Irreversible inhibitors of the EGFreceptor may circumvent acquired resistance togefitinib. Proc. Natl Acad. Sci. USA 102, 7665-7670(2005).
137. Carter, T. A. et al. Inhibition of drug-resistant mutantsof ABL, KIT, and EGF receptor kinases. Proc. NatlAcad. Sci. USA 102, 11011-11016 (2005).
138. Sharma, S. V., Bell, D. W., Settleman, J. & Haber, D. A. Epidermal growth factor receptormutations in lung cancer. Nature Rev. Cancer 7,169-181 (2007).
139. Wong, K. K. et al. A phase I study with neratinib(HKI-272), an irreversible pan ErbB receptor tyrosinekinase inhibitor, in patients with solid tumors. Clin. Cancer Res. 15, 2552-2558 (2009).
140. Sequist, L. V. et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of aPhase II trial in patients with advancednon-small-cell lung cancer. J. Clin. Oncol. 28,3076-3083 (2010).
141. Li, D. et al. BIBW2992, an irreversible EGFR/HER2inhibitor highly effective in preclinical lung cancermodels. Oncogene 27, 4702-4711 (2008).
142. Engelman, J. A. et al. PF00299804, an irreversiblepan-ERBB inhibitor, is effective in lung cancermodels with EGFR and ERBB2 mutations that areresistant to gefitinib. Cancer Res. 67, 11924-11932(2007).
143. Gonzales, A. J. et al. Antitumor activity andpharmacokinetic properties of PF-00299804, asecond-generation irreversible pan-erbB receptortyrosine kinase inhibitor. Mol. Cancer Ther. 7,1880-1889 (2008).
144. Ogino, A. et al. Emergence of epidermal growth factorreceptor T790M mutation during chronic exposure togefitinib in a non small cell lung cancer cell line. Cancer Res. 67, 7807-7814 (2007).
145. Godin-Heymann, N. et al. The T790M 'gatekeeper'mutation in EGFR mediates resistance to lowconcentrations of an irreversible EGFR inhibitor. Mol. Cancer Ther. 7, 874-879 (2008).
146. Ercan, D. et al. Amplification of EGFR T790M causesresistance to an irreversible EGFR inhibitor. Oncogene29, 2346-2356 (2010).
147. Zhou, W. et al. Novel mutant-selective EGFR kinaseinhibitors against EGFR T790M. Nature 462,1070-1074 (2009).
148. Li, D. et al. Bronchial and peripheral murine lungcarcinomas induced by T790M-L858R mutant EGFRrespond to HKI-272 and rapamycin combinationtherapy. Cancer Cell 12, 81-93 (2007).
149. Comoglio, P. M., Giordano, S. & Trusolino, L. Drugdevelopment of MET inhibitors: targeting oncogeneaddiction and expedience. Nature Rev. Drug Discov. 7,504-516 (2008).
150. Foo, J. & Michor, F. Evolution of resistance to targetedanti-cancer therapies during continuous and pulsedadministration strategies. PLoS Comput. Biol. 5,e1000557 (2009).
151. Shah, N. P. et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid anddurable cytogenetic responses and hightransformation-free survival rates in chronic phasechronic myeloid leukemia patients with resistance,suboptimal response or intolerance to imatinib. Haematologica 95, 232-240 (2010).
152. Schiller, J. H. et al. Comparison of four chemotherapyregimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 346, 92-98 (2002).
153. Sandler, A. et al. Paclitaxel-carboplatin alone or withbevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542-2550 (2006).
154. Amado, R. G. et al. Wild-type KRAS is required forpanitumumab efficacy in patients with metastaticcolorectal cancer. J. Clin. Oncol. 26, 1626-1634(2008).
155. Van Cutsem, E. et al. Cetuximab and chemotherapy asinitial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408-1417 (2009).
156. Eberhard, D. A. et al. Mutations in the epidermalgrowth factor receptor and in KRAS are predictive andprognostic indicators in patients with non-small-celllung cancer treated with chemotherapy alone and incombination with erlotinib. J. Clin. Oncol. 23,5900-5909 (2005).
157. Kim, E. S. et al. Gefitinib versus docetaxel in previouslytreated non-small-cell lung cancer (INTEREST): arandomised Phase III trial. Lancet 372, 1809-1818(2008).
158. Gatzemeier, U. et al. Phase III study of erlotinib incombination with cisplatin and gemcitabine inadvanced non-small-cell lung cancer: the Tarceva LungCancer Investigation Trial. J. Clin. Oncol. 25,1545-1552 (2007).
159. Zhu, C. Q. et al. Role of KRAS and EGFR asbiomarkers of response to erlotinib in National CancerInstitute of Canada Clinical Trials Group StudyBR.21. J. Clin. Oncol. 26, 4268-4275 (2008).
160. Bell, D. W. et al. Epidermal growth factor receptormutations and gene amplification in non-small-celllung cancer: molecular analysis of the IDEAL/INTACTgefitinib trials. J. Clin. Oncol. 23, 8081-8092 (2005).
161. Shah, N. P. et al. Multiple BCR-ABL kinase domainmutations confer polyclonal resistance to the tyrosinekinase inhibitor imatinib (STI571) in chronic phaseand blast crisis chronic myeloid leukemia. Cancer Cell2, 117-125 (2002).
162. Branford, S. et al. Detection of BCR-ABL mutations inpatients with CML treated with imatinib is virtuallyalways accompanied by clinical resistance, andmutations in the ATP phosphate-binding loop (P-loop)are associated with a poor prognosis. Blood 102,276-283 (2003).
163. Antonescu, C. R. et al. Acquired resistance to imatinibin gastrointestinal stromal tumor occurs throughsecondary gene mutation. Clin. Cancer Res. 11,4182-4190 (2005).
164. Wardelmann, E. et al. Polyclonal evolution of multiplesecondary KIT mutations in gastrointestinal stromaltumors under treatment with imatinib mesylate. Clin. Cancer Res. 12, 1743-1749 (2006).
165. Cowan-Jacob, S. W. et al. Structural biologycontributions to the discovery of drugs to treat chronicmyelogenous leukaemia. Acta Crystallogr. D Biol. Crystallogr. 63, 80-93 (2007).
166. Mol., C. D. et al. Structural basis for the autoinhibitionand STI-571 inhibition of c-Kit tyrosine kinase. J. Biol. Chem. 279, 31655-31663 (2004).
167. Pettersen, E. F. et al. UCSF Chimera a visualizationsystem for exploratory research and analysis. J. Comput. Chem. 25, 1605-1612 (2004).
168. Giaccone, G. et al. Gefitinib in combination withgemcitabine and cisplatin in advanced non-small-celllung cancer: a Phase III trial \-INTACT 1. J. Clin. Oncol. 22, 777-784 (2004).
169. Herbst, R. S. et al. Gefitinib in combination withpaclitaxel and carboplatin in advanced non-small-celllung cancer: a Phase III trial \-I NTACT 2. J. Clin. Oncol. 22, 785-794 (2004).
170. Herbst, R. S. et al. TRIBUTE: a Phase III trial oferlotinib hydrochloride (OSI-774) combined withcarboplatin and paclitaxel chemotherapy in advancednon-small-cell lung cancer. J. Clin. Oncol. 23,5892-5899 (2005).
171. Pirker, R. et al. Cetuximab plus chemotherapy inpatients with advanced non-small-cell lung cancer(FLEX): an open-label randomised Phase III trial. Lancet 373, 1525-1531 (2009).
172. Wakeling, A. E. et al. ZD1839 (Iressa): an orally activeinhibitor of epidermal growth factor signaling withpotential for cancer therapy. Cancer Res. 62,5749-5754 (2002).
173. Hidalgo, M. et al. Phase I and pharmacologic study ofOSI-774, an epidermal growth factor receptortyrosine kinase inhibitor, in patients with advancedsolid malignancies. J. Clin. Oncol. 19, 3267-3279(2001).
174. Gendreau, S. B. et al. Inhibition of the T790Mgatekeeper mutant of the epidermal growth factorreceptor by EXEL-7647. Clin. Cancer Res. 13,3713-3723 (2007).
175. Ryan, A. J. & Wedge, S. R. ZD6474 a novelinhibitor of VEGFR and EGFR tyrosine kinase activity. Br. J. Cancer 92 (Suppl. 1), 6-13 (2005).
176. Xia, W. et al. Anti-tumor activity of GW572016: adual tyrosine kinase inhibitor blocks EGF activation ofEGFR/erbB2 and downstream Erk1/2 and AKTpathways. Oncogene 21, 6255-6263 (2002).
177. Erlichman, C. et al. Phase I study of EKB-569, anirreversible inhibitor of the epidermal growth factorreceptor, in patients with advanced solid tumors. J. Clin. Oncol. 24, 2252-2260 (2006).
178. Rabindran, S. K. et al. Antitumor activity of HKI-272,an orally active, irreversible inhibitor of the HER-2tyrosine kinase. Cancer Res. 64, 3958-3965(2004).
179. Allen, L. F., Eiseman, I. A., Fry, D. W. & Lenehan, P. F. CI-1033, an irreversible pan-erbB receptor inhibitorand its potential application for the treatment ofbreast cancer. Semin. Oncol. 30, 65-78 (2003).