Journal of Molecular Medicine

, Volume 92, Issue 7, pp 697–707 | Cite as

Oncogenic drivers, targeted therapies, and acquired resistance in non-small-cell lung cancer



In the past decade, a shift toward targeted therapies in non-small-cell lung cancer following molecular profiling has dramatically changed the way advanced adenocarcinoma is treated. However, tumor cells inevitably acquire resistance to such therapies, circumventing any sustained clinical benefit. As the genomic classification of lung cancer continues to evolve and as the mechanisms of acquired resistance to targeted therapies become elucidated and more improved target-specific drugs come into sight, the future will see more promising results from the clinic through the development of new therapeutic strategies to overcome, or prevent the development of, resistance for lung cancer patients.


Non-small-cell lung cancer Oncogenic drivers TKIs RTKs Acquired resistance 


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64:9–29PubMedCrossRefGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRefGoogle Scholar
  3. 3.
    Shames D, Wistuba I (2014) The evolving genomic classification of lung cancer. J Pathol 232:121–133PubMedCrossRefGoogle Scholar
  4. 4.
    American Cancer Society (2012) Cancer facts and figures 2012. [Accessed January 13, 2014]. Available from:
  5. 5.
    Hrustanovic G, Lee B, Bivona T (2013) Mechanisms of resistance to EGFR targeted therapies. Cancer Biol Ther 14:304–314PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Spiro S, Silvestri G (2005) One hundred years of lung cancer. Am J Respir Crit Care Med 172:523–529PubMedCrossRefGoogle Scholar
  7. 7.
    Metro G, Cappuzzo F (2009) Emerging drugs for small-cell lung cancer. Expert Opin Emerg Drugs 14:591–606PubMedCrossRefGoogle Scholar
  8. 8.
    Kelly K, Crowley J, Bunn P Jr, Presant C, Grevstad P, Moinpour C, Ramsey S, Wozniak A, Weiss G, Moore D et al (2001) Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19:3210–3218PubMedGoogle Scholar
  9. 9.
    Schiller J, Harrington D, Belani C, Langer C, Sandler A, Krook J, Zhu J, Johnson D (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98PubMedCrossRefGoogle Scholar
  10. 10.
    Scagliotti G, De Marinis F, Rinaldi M, Crino L, Gridelli C, Ricci S, Matano E, Boni C, Marangolo M, Failla G et al (2002) Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 20:4285–4291PubMedCrossRefGoogle Scholar
  11. 11.
    Bonanno L, Favaretto A, Rosell R (2014) Platinum drugs and DNA repair mechanisms in lung cancer. Anticancer Res 34:493–502PubMedGoogle Scholar
  12. 12.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson D (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550PubMedCrossRefGoogle Scholar
  13. 13.
    Pao W, Chmielecki J (2010) Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 11:760–774CrossRefGoogle Scholar
  14. 14.
    Sawyers C (2004) Targeted cancer therapy. Nature 432:294–297PubMedCrossRefGoogle Scholar
  15. 15.
    Weinstein I (2002) Addiction to oncogenes—the Achilles heal of cancer. Science 297:63–64PubMedCrossRefGoogle Scholar
  16. 16.
    Niederst M, Engelman J (2013) Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal 6:re6PubMedCrossRefGoogle Scholar
  17. 17.
    Thomas A, Rajan A, Lopez-Chavez A, Wang Y, Giaccone G (2013) From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma. Ann Oncol 24:577–585PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Kim E, Herbst R, Wistuba I, Lee J, Blumenschein G Jr, Tsao A, Stewart D, Hicks M, Erasmus J Jr, Gupta S et al (2011) The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 1:44–53PubMedCrossRefGoogle Scholar
  19. 19.
    Cardarella S, Ortiz T, Joshi V, Butaney M, Jackman D, Kwiakowski D, Yeap B, Jänne P, Linderman N, Johnson B (2012) The introduction of systematic genomic testing for patients with non-small-cell lung cancer. J Thorac Oncol 12:1767–1774CrossRefGoogle Scholar
  20. 20.
    Linderman N, Cagle P, Beasley M, Chitale D, Dacic S, Giaccone G, Jenkins R, Kwiatkowski D, Saldivar J, Squire J et al (2013) Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn 15:415–453CrossRefGoogle Scholar
  21. 21.
    Linderman N, Cagle P, Beasley M, Chitale D, Dacic S, Giaccone G, Jenkins R, Kwiatkowski D, Saldivar J, Squire J et al (2013) Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 8:823–859CrossRefGoogle Scholar
  22. 22.
    Linderman N, Cagle P, Beasley M, Chitale D, Dacic S, Giaccone G, Jenkins R, Kwiatkowski D, Saldivar J, Squire J et al (2013) Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 137:828–860CrossRefGoogle Scholar
  23. 23.
    Gadgeel S, Chen W, Cote ML, Bollig-Fischer A, Land S, Schwartz AG, Bepler G (2013) Fibroblast growth factor receptor 1 amplification in non-small cell lung cancer by quantitative real-time PCR. PLoS One 8:e79820PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, Mahale S, Davies K, Aisner D, Pilling A et al (2013) Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19:1469–1472PubMedCrossRefGoogle Scholar
  25. 25.
    Berger A, Imielinski M, Duke F, Wala J, Kaplan N, Shi G, Andres D, Meyerson M (2014) Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogenesis. doi:10.1038/onc.2013.581
  26. 26.
    Weir B, Woo M, Getz G, Perner S, Ding L, Beroukhim R, Lin W, Province M, Kraja A, Johnson L et al (2007) Characterizing the cancer genome in lung adenocarcinoma. Nature 450:893–898PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Weber B, Hager H, Sorensen B, McCulloch T, Mellemgaard A, Khalil A, Nexo E, Meldgaard P (2014) EGFR mutation frequency and effectiveness of erlotinib: a prospective observational study in Danish patients with non-small cell lung cancer. Lung Cancer 83:224–230PubMedCrossRefGoogle Scholar
  28. 28.
    Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Dogan S, Shen R, Ang DC, Johnson ML, D’Angelo SP, Paik PK, Brzostowski EB, Riely GJ, Kris MG, Zakowski MF et al (2012) Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res 18:6169–6177PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Lynch T, Bell D, Sordella R, Gurubhagavatula S, Okimoto R, Brannigan B, Harris P, Haserlat S, Supko J, Haluska F et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139PubMedCrossRefGoogle Scholar
  31. 31.
    Paez J, Jänne P, Lee J, Tracy S, Greulich H, Gabriel S, Herman P, Kaye F, Lindeman N, Boggon T et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedCrossRefGoogle Scholar
  32. 32.
    Mok T, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y et al (2009) Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957PubMedCrossRefGoogle Scholar
  33. 33.
    Sequist L, Yang J, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater S, Orlov S, Tsai C, Boyer M et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334PubMedCrossRefGoogle Scholar
  34. 34.
    Fukuoka M, Wu Y, Thongprasert S, Sunpaweravong P, Leong S, Sriuranpong V, Chao T, Nakagawa K, Chu D, Saijo N et al (2011) 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 29:2866–2874PubMedCrossRefGoogle Scholar
  35. 35.
    Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C et al (2012) First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trail in never-smokers with adenocarcinoma of the lung. J Clin Oncol 10:1122–1128CrossRefGoogle Scholar
  36. 36.
    Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T et al (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol 11:121–128PubMedCrossRefGoogle Scholar
  37. 37.
    Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388PubMedCrossRefGoogle Scholar
  38. 38.
    Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM et al (2012) 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 13:239–246PubMedCrossRefGoogle Scholar
  39. 39.
    Zhou C, Wu Y, Chen G, Feng J, Liu X, Wang C, Zhang S, Wang J, Zhou S, Ren S et al (2011) 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 12:735–742PubMedCrossRefGoogle Scholar
  40. 40.
    Jackman D, Pao W, Riely G, Engelman J, Kris M, Jänne P, Lynch T, Johnson B, Miller V (2010) Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 28:357–360PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Kobayashi S, Boggon T, Dayaram T, Jänne P, Kocher O, Meyerson M, Johnson B, Eck M, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792PubMedCrossRefGoogle Scholar
  42. 42.
    Pao W, Miller V, Politi K, Riely G, Somwar R, Zakowski M, Kris M, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Sequist L, Waltman B, Dias-Santagata D, Digumarthy S, Turke A, Fidias P, Bergethon K, Shaw A, Gettinger S, Cosper A et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 75:ra26Google Scholar
  44. 44.
    Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K, Meyerson M, Eck M (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci 105:2070–2075PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, Suehisa H, Ouchida M, Aoe K, Aoe M et al (2006) Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 66:7854–7858PubMedCrossRefGoogle Scholar
  46. 46.
    Balak M, Gong Y, Riely G, Somwar R, Li A, Zakowski M, Chiang A, Yang G, Ouerfelli O, Kris M et al (2006) NovelD761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494–6501PubMedCrossRefGoogle Scholar
  47. 47.
    Bean J, Riely G, Balak M, Marks J, Ladanyi M, Miller V, Pao W (2008) 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 14:7519–7525PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Costa D, Schumer S, Tenen D, Kobayashi S (2008) 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 26:1182–1184PubMedCrossRefGoogle Scholar
  49. 49.
    Engelman J, Zejnullahu K, Gale C, Lifshits E, Gonzales A, Shimamura T, Zhao F, Vincent P, Naumov G, Bradner J et al (2007) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67:11924–11932PubMedCrossRefGoogle Scholar
  50. 50.
    Water A, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, Dubrovskiy A, Labenski M, Zhu Z, Wang Z et al (2013) Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 3:1404–1415CrossRefGoogle Scholar
  51. 51.
    Ranson M, Pao W, Kim D, Kim S, Ohe Y, Felip E, Planchard D, Ghiorghiu S, Cantarini M, Jänne P (2013) LATE BREAKING ABSTRACT: 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). Eur Cancer Congr Abstr: 33.Google Scholar
  52. 52.
    Chong C, Jänne P (2013) The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 19:1389–1400PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Engelman J, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park J, Lindeman N, Gale C, Zhao X, Christensen J et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043PubMedCrossRefGoogle Scholar
  54. 54.
    Bean J, Brennan C, Shih J, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S et al (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci 104:20932–20937PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Turke B, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L et al (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17:77–88PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, Ogino H, Kakiuchi S, Hanibuchi M, Nishioka Y et al (2008) Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 68:9479–9487PubMedCrossRefGoogle Scholar
  57. 57.
    Takezawa K, Pirazzoli V, Arcila M, Nebhan C, Song X, de Stanchina E, Ohashi K, Janjigian Y, Spitzler P, Melnick M et al (2012) 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 2:922–933PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine AD, Rho JK et al (2012) Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 44:852–860PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Chaft J, Arcila M, Paik P, Lau C, Riely G, Pietanza M, Zakowski M, Rusch V, Sima C, Ladanyi M et al (2012) Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther 11:485–491PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Yu H, Arcila M, Rekhtman N, Sima C, Zakowski M, Pao W, Kris M, Miller V, Ladanyi M, Riely G (2013) 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 19:2240–2247PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Hallberg B, Palmer R (2013) Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 13:685–700PubMedCrossRefGoogle Scholar
  62. 62.
    Soda M, Choi Y, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566PubMedCrossRefGoogle Scholar
  63. 63.
    Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–1203PubMedCrossRefGoogle Scholar
  64. 64.
    Li Y, Ye X, Liu J, Zha J, Pei L (2011) Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia 13:1–11PubMedCentralPubMedGoogle Scholar
  65. 65.
    Wong D, Leung E, So K, Tam I, Sihoe A, Cheng L, Ho K, Au J, Chung L, Pik Wong M (2009) The EML4-ALKfusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115:1723–1733PubMedCrossRefGoogle Scholar
  66. 66.
    Gainor J, Varghese A, Ou S, Kabraji S, Awad M, Katayama R, Pawlak A, Mino-Kenudson M, Yeap B, Riely G et al (2013) ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 19:4273–4281PubMedCrossRefGoogle Scholar
  67. 67.
    Zhang N, Liu Y, Ma L, Wang L, Hao X, Yuan Z, Lin D, Li D, Zhou Y, Lin H et al (2014) The molecular detection and clinical significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK targeted therapy. PLoS One 9:e84501PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Kwak E, Bang Y, Camidge D, Shaw A, Solomon B, Maki R, Ou S, Dezube B, Jänne P, Costa D et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Shaw A, Kim D, Nakagawa K, Seto T, Crinó L, Ahn M, De Pas T, Besse B, Solomon B, Blackhall F et al (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385–2394PubMedCrossRefGoogle Scholar
  70. 70.
    Shaw T, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M et al (2011) Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12:1004–1012PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C et al (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 120:ra17Google Scholar
  72. 72.
    Doebele R, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA et al (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Choi Y, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H et al (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734–1739PubMedCrossRefGoogle Scholar
  74. 74.
    Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S, Zheng W, Lathan C, Marcoux JP, Du J, Okuda K et al (2011) A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 71:6051–6060PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Tartarone A, Lazzari C, Lerose R, Conteduca V, Improta G, Zupa A, Bulotta A, Aieta M, Gregorc V (2013) Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib. Lung Cancer 81:328–336PubMedCrossRefGoogle Scholar
  76. 76.
    Bos M, Gardizi M, Schildhaus HU, Heukamp LC, Geist T, Kaminsky B, Zander T, Nogova L, Scheffler M, Dietlein M, Kobe C, Holstein A, Maintz D, Büttner R, Wolf J (2013) Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. Lung Cancer 81:142-143.Google Scholar
  77. 77.
    Shaw A, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T et al (2014) Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189–1197PubMedCrossRefGoogle Scholar
  78. 78.
    Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M et al (2013) CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 14:590–598PubMedCrossRefGoogle Scholar
  79. 79.
    Ou S, Gadgeel S, Chiappori A, Riely G, Lee R, Garcia L, Tatsuno M, Tanaka T, Gandhi L (2013) LATE BREAKING ABSTRACT: safety and efficacy analysis of RO5424802/CH5424802 in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients who have failed crizotinib in a dose-finding phase I study (AF-002JG, NCT01588028). Eur Cancer Congr Abstr 44.Google Scholar
  80. 80.
    Camidge D, Bazhenova L, Salgia R, Weiss G, Langer C, Shaw A, Narasimhan N, Dorer D, Rivera V, Zhang J et al (2013) First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: updated results. J Clin Oncol Abstr 31:8031Google Scholar
  81. 81.
    Patnaik A, LoRusso P, Ball H, Bahceci E, Yuen G, Papadopoulos K, Kittaneh M, Tolcher A (2013) Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial. J Clin Oncol Abstr 31:2606Google Scholar
  82. 82.
    Brahmer J, Tykodi S, Chow L, Hwu W, Topalian S, Hwu P, Drake C, Camacho L, Kauh J, Odunsi K et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y (2011) CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 19:679–690PubMedCrossRefGoogle Scholar
  84. 84.
    Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H et al (2012) RET, ROS1 and ALK fusions in lung cancer. Nat Med 18:378–381PubMedCrossRefGoogle Scholar
  85. 85.
    Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863–870PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Suehara Y, Arcila M, Wang L, Hasanovic A, Ang D, Ito T, Kimura Y, Drilon A, Guha U, Rusch V et al (2012) Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin Cancer Res 18:6599–6608PubMedCrossRefGoogle Scholar
  87. 87.
    Jun H, Johnson H, Bronson RT, de Feraudy S, White F, Charest A (2012) The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation. Cancer Res 72:3764–3767PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Chin L, Soo R, Soong R, Ou S (2012) Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. J Thorac Oncol 7:1625–1630PubMedCrossRefGoogle Scholar
  89. 89.
    Ou S, Bang Y, Camidge D, Riely G, Salgia R, Shapiro G, Solomon B, Engelman J, Kwak E, Clark J et al (2013) Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC). J Clin Oncol Abstr 31:8032Google Scholar
  90. 90.
    Awad M, Katayama R, McTigue M, Liu W, Deng YL, Brooun A, Friboulet L, Huang D, Falk M, Timofeevski S et al (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368:2395–2401PubMedCrossRefGoogle Scholar
  91. 91.
    Davies K, Mahale S, Astling D, Aisner D, Le A, Hinz T, Vaishnavi A, Bunn P Jr, Heasley L, Tan A et al (2013) Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 8:e82236PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, Sakamoto H, Tsuta K, Furuta K, Shimada Y et al (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med 18:375–377PubMedCrossRefGoogle Scholar
  93. 93.
    Pao W, Hutchinson K (2012) Chipping away at the lung cancer genome. Nat Med 18:349–351PubMedCrossRefGoogle Scholar
  94. 94.
    Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, Ross J, Miller V, Ginsberg M, Zakowski M et al (2013) Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov 3:630–635PubMedCrossRefGoogle Scholar
  95. 95.
    Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, Del Grammastro M, Sciarrotta M, Buttitta F, Incarbone M et al (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27:1667–1674PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Sadiq A, Salgia R (2013) MET as a possible target for non-small-cell lung cancer. J Clin Oncol 31:1089–1096PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Basilico C, Pennacchietti S, Vigna E, Chiriaco C, Arena S, Bardelli A, Valdembri D, Serini G, Michieli P (2013) Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin Cancer Res 19:2381–2392PubMedCrossRefGoogle Scholar
  98. 98.
    Katayama R, Aoyama A, Yamori T, Qi J, Oh-hara T, Song Y, Engelman JA, Fujita N (2013) Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res 73:3087–3096PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Ou S, Kwak E, Siwak-Tapp C, Dy J, Bergethon K, Clark J, Camidge D, Solomon B, Maki R, Bang Y et al (2011) Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 6:942–946PubMedCrossRefGoogle Scholar
  100. 100.
    Spigel D, Ervin T, Ramlau R, Daniel D, Goldschmidt J Jr, Blumenschein G Jr, Krzakowski M, Robinet G, Godbert B, Barlesi F et al (2013) Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 31:4105–4114PubMedCrossRefGoogle Scholar
  101. 101.
    Cepero V, Sierra J, Corso S, Ghiso E, Casorzo L, Perera T, Comoglio P, Giordano S (2010) MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res 70:7580–7590PubMedCrossRefGoogle Scholar
  102. 102.
    McDermott U, Pusapati R, Christensen J, Gray N, Settleman J (2010) Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. Cancer Res 70:1625–1634PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H, Wistuba I, Fong K, Toyooka S, Shimizu N et al (2005) Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65:1642–1646PubMedCrossRefGoogle Scholar
  104. 104.
    Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O'Meara S, Smith R, Parker A et al (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431:525–526PubMedCrossRefGoogle Scholar
  105. 105.
    Mazières J, Peters S, Lepage B, Cortot A, Barlesi F, Beau-Faller M, Besse B, Blons H, Mansuet-Lupo A, Urban T et al (2013) Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 31:1997–2003PubMedCrossRefGoogle Scholar
  106. 106.
    Ross H, Blumenschein G Jr, Aisner J, Damjanov N, Dowlati A, Garst J, Rigas J, Smylie M, Hassani H, Allen K et al (2010) Randomized phase II multicenter trial of two schedules of lapatinib as first- or second-line monotherapy in patients with advanced or metastatic non-small cell lung cancer. Clin Cancer Res 16:1938–1949PubMedCrossRefGoogle Scholar
  107. 107.
    Davies H, Bignell G, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett M, Bottomley W et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954PubMedCrossRefGoogle Scholar
  108. 108.
    Paik P, Arcila M, Fara M, Sima C, Miller V, Kris M, Ladanyi M, Riely G (2011) Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 29:2046–2051PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Sosman J, Kim K, Schuchter L, Gonzalez R, Pavlick A, Weber J, McArthur G, Hutson T, Moschos S, Flaherty K et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, Viola P, Pullara C, Mucilli F, Buttitta F (2011) Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 29:3574–3579PubMedCrossRefGoogle Scholar
  111. 111.
    Planchard D, Mazieres J, Riely G, Rudin C, Barlesi F, Quoix E, Souquet P, Socinski M, Switzky J, Ma B et al (2013) Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. ASCO Meet Abstr 31:8009Google Scholar
  112. 112.
    Rudin C, Hong K, Streit M (2013) Molecular characterization of acquired resistance to the BRAF inhibitor dabrafenib in a patient with BRAF-mutant non-small-cell lung cancer. J Thorac Oncol 8:e41–e42PubMedCentralPubMedGoogle Scholar
  113. 113.
    Oxnard G, Binder A, Jänne P (2013) New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol 31:1097–1104PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Hammerman P, Sos M, Ramos A, Xu C, Dutt A, Zhou W, Brace L, Woods B, Lin W, Zhang J et al (2011) Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 1:78–89PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Dutt A, Ramos A, Hammerman P, Mermel C, Cho J, Sharifnia T, Chande A, Tanaka KE, Stransky N, Greulich H et al (2011) Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 6:e20351PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Sliwkowski M, Mellman I (2013) Antibody therapeutics in cancer. Science 341:1192–1198PubMedCrossRefGoogle Scholar
  117. 117.
    Topalian S, Hodi F, Brahmer J, Gettinger S, Smith D, McDermott D, Powderly J, Carvajal R, Sosman J, Atkins M et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS et al (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–112PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Georgetown UniversityWashingtonUSA

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