Mechanisms of Resistance to Target Therapies in Non-small Cell Lung Cancer

  • Francesco Facchinetti
  • Claudia Proto
  • Roberta Minari
  • Marina Garassino
  • Marcello TiseoEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)


Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i.e. MET amplification, KRAS mutations); (3) phenotype transformation (to small cell lung cancer, epithelial–mesenchymal transition). These basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. Novel-generation molecules include osimertinib, for EGFR-T790M-positive patients, and new ALK-TKIs. Nevertheless, the possible concomitant presence of multiple resistance mechanisms, as well as their heterogeneity among cells and disease localizations, makes research in this field particularly arduous. In this chapter, available evidence and perspectives concerning precise mechanisms of escape to pharmacological inhibition in oncogene-addicted NSCLC are reported for single targets, including but not limited to EGFR and ALK.


ALK EGFR NSCLC Resistance mechanisms ROS-1 T790M 


  1. Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF et al (2011) Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 17:1169–1180PubMedPubMedCentralGoogle Scholar
  2. Awad MM (2016) Impaired c-Met receptor degradation mediated by MET exon 14 mutations in non-small-cell lung cancer. J Clin Oncol 34:879–881PubMedGoogle Scholar
  3. Awad MM, Katayama R, McTigue M, Liu W, Deng Y-L, Brooun A et al (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368:2395–2401PubMedGoogle Scholar
  4. Bahcall M, Sim T, Paweletz CP, Patel JD, Alden RS, Kuang Y et al (2016) Acquired METD1228V mutation and resistance to MET inhibition in lung cancer. Cancer Discov 6:1334–1341PubMedPubMedCentralGoogle Scholar
  5. Ballard P, Yates JWT, Yang Z, Kim DW, Yang JCH, Cantarini M et al (2016) Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 22:5130–5140PubMedGoogle Scholar
  6. Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H et al (2016) Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French cooperative thoracic intergroup (IFCT). Lancet 387:1415–1426PubMedGoogle Scholar
  7. Benderra MA, Aspeslagh S, Postel-Vinay S, Bigot L, De Baere T, Loriot Y et al (2016) Acquired EGFR mutation as the potential resistance driver to crizotinib in a MET-mutated tumor. J Thorac Oncol 11:e21–e23PubMedGoogle Scholar
  8. Bergethon K, Shaw AT, Ou S-HI, Katayama R, Lovly CM, McDonald NT et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863–870PubMedPubMedCentralGoogle Scholar
  9. Campo M, Gerber D, Gainor JF, Heist RS, Temel JS, Shaw AT et al (2016) Acquired resistance to first-line afatinib and the challenges of prearranged progression biopsies. J Thorac Oncol 11:2022–2026PubMedGoogle Scholar
  10. Cargnelutti M, Corso S, Pergolizzi M, Mévellec L, Aisner DL, Dziadziuszko R et al (2015) Activation of RAS family members confers resistance to ROS1 targeting drugs. Oncotarget 6:5182–5194PubMedGoogle Scholar
  11. Caumont C, Veillon R, Gros A, Laharanne E, Bégueret H, Merlio JP (2016) Neuroendocrine phenotype as an acquired resistance mechanism in ALK-rearranged lung adenocarcinoma. Lung Cancer 92:15–18PubMedGoogle Scholar
  12. Chabon JJ, Simmons AD, Lovejoy AF, Esfahani MS, Newman AM, Haringsma HJ et al (2016) Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun 7:11815PubMedPubMedCentralGoogle Scholar
  13. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T et al (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363:1734–1739Google Scholar
  14. Chong CR, Bahcall M, Capelletti M, Kosaka T, Ercan D, Sim T et al (2017) Identification of existing drugs that effectively target NTRK1- and ROS1-rearrangements in lung cancer. Clin Cancer Res 23:204–213PubMedGoogle Scholar
  15. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W et al (2011) CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 29:e443–e445PubMedGoogle Scholar
  16. Cross DAE, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ et al (2014) AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4:1046–1061PubMedPubMedCentralGoogle Scholar
  17. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A (2013) Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 10:472–484PubMedGoogle Scholar
  18. Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL et al (2014) Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 346:1480–1486PubMedPubMedCentralGoogle Scholar
  19. Davare MA, Vellore NA, Wagner JP, Eide CA, Goodman JR, Drilon A et al (2015) Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors. Proc Natl Acad Sci 112:E5381–E5390PubMedGoogle Scholar
  20. Davies KD, Mahale S, Astling DP, Aisner DL, Le AT, Hinz TK et al (2013) Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 8:1–13Google Scholar
  21. Del Re M, Tiseo M, Bordi P, D’Incecco A, Camerini A, Petrini I et al (2016) Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA. Oncotarget [Epub ahead of print]Google Scholar
  22. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ et al (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482PubMedPubMedCentralGoogle Scholar
  23. Douillard JJ-Y, Ostoros G, Cobo M, Ciuleanu T, Cole R, McWalter G et al (2014) Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol 9:1345–1353PubMedPubMedCentralGoogle Scholar
  24. Drilon A, Somwar R, Wagner JP, Vellore NA, Eide CA, Zabriskie MS et al (2016a) A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res 22:2351–2358PubMedGoogle Scholar
  25. Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M et al (2016b) Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 17:1653–1660PubMedPubMedCentralGoogle Scholar
  26. Drilon A, Cappuzzo F, Ou SICD (2017) Targeting MET in lung cancer: will expectations finally be MET? J Thorac Oncol 12:15–26PubMedGoogle Scholar
  27. Dziadziuszko R, Le AT, Wrona A, Jassem J, Camidge DR, Varella-Garcia M et al (2016) An activating KIT mutation induces crizotinib resistance in ROS1-positive lung cancer. J Thorac Oncol 11:1273–1281PubMedPubMedCentralGoogle Scholar
  28. Eberlein CA, Stetson D, Markovets AA, Al-Kadhimi KJ, Lai Z, Fisher PR et al (2015) Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res 75:2489–2500PubMedPubMedCentralGoogle Scholar
  29. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043Google Scholar
  30. Ercan D, Choi HG, Yun CH, Capelletti M, Xie T, Eck MJ et al (2015) EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res 21:3913–3923PubMedPubMedCentralGoogle Scholar
  31. Facchinetti F, Tiseo M, Di Maio M, Graziano P, Novello S (2016a) Tackling ALK in non-small cell lung cancer: the role of novel inhibitors. Transl Lung Cancer Res 5:301–321PubMedPubMedCentralGoogle Scholar
  32. Facchinetti F, Loriot Y, Kuo MS, Mahjoubi L, Lacroix L, Planchard D et al (2016b) Crizotinib-resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1- and ALK-rearranged lung cancers. Clin Cancer Res 15:5983–5991Google Scholar
  33. Facchinetti F, Rossi G, Bria E, Soria JC, Besse B, Minari R et al (2017) Oncogene addiction in non-small cell lung cancer: focus on ROS1 inhibition. Cancer Treat Rev. doi: 10.1016/j.ctrv.2017.02.010 PubMedGoogle Scholar
  34. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS et al (2014) The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 4:662–673PubMedPubMedCentralGoogle Scholar
  35. Fujita S, Masago K, Katakami N, Yatabe Y (2016) Transformation to SCLC after treatment with the ALK inhibitor alectinib. J Thorac Oncol 11:e67–e72PubMedGoogle Scholar
  36. Gainor JF, Varghese AM, Ou SHI, Kabraji S, Awad MM, Katayama R 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 19:4273–4281PubMedGoogle Scholar
  37. Gainor JF, Niederst MJ, Lennerz JK, Dagogo-Jack I, Stevens S, Shaw AT et al (2016a) Dramatic response to combination erlotinib and crizotinib in a patient with advanced, EGFR-mutant lung cancer harboring de novo MET amplification. J Thorac Oncol 11:e83–e85PubMedGoogle Scholar
  38. Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R et al (2016b) Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov 6:1118–1133PubMedPubMedCentralGoogle Scholar
  39. Gainor JF, Friboulet L, Yoda S, Dardaei Alghalandis L, Farago AF, Logan J et al (2016c) Frequency and spectrum of ROS1 resistance mutations in ROS1-positive lung cancer patients progressing on crizotinib. J Clin Oncol 34:(suppl; abstr 9072)Google Scholar
  40. Gatalica Z, Burnett K, Bender R, Feldman R, Vranic S, Reddy S (2015) BRAF mutations are potentially targetable alterations in a wide variety of solid cancers. Eur J Cancer 51(suppl 3):S31Google Scholar
  41. Goss G, Tsai C-M, Shepherd FA, Bazhenova L, Lee JS, Chang G-C et al (2016) Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 17:1643–1652PubMedGoogle Scholar
  42. Ham JS, Kim S, Kim HK, Byeon S, Sun JM, Lee SH et al (2016) Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment. J Thorac Oncol 11:e1–e4PubMedGoogle Scholar
  43. Haratani K, Hayashi H, Watanabe S, Kaneda H, Yoshida T, Takeda M et al (2016) Two cases of EGFR mutation-positive lung adenocarcinoma that transformed into squamous cell carcinoma: successful treatment of one case with rociletinib. Ann Oncol 27:200–202PubMedGoogle Scholar
  44. Hata A, Katakami N, Yoshioka H, Kaji R, Masago K, Fujita S et al (2015) Spatiotemporal T790M heterogeneity in individual patients with EGFR-mutant non–small-cell lung cancer after acquired resistance to EGFR-TKI. J Thorac Oncol 10:1553–1559PubMedGoogle Scholar
  45. Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE et al (2016) Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 22:262–269PubMedPubMedCentralGoogle Scholar
  46. Heist RS, Sequist LV, Borger D, Gainor JF, Arellano RS, Le LP et al (2016) Acquired resistance to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol 11:1242–1245PubMedGoogle Scholar
  47. Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM et al (2010) Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res 16:5873–5882PubMedPubMedCentralGoogle Scholar
  48. Heuckmann JM, Balke-Want H, Malchers F, Peifer M, Sos ML, Koker M et al (2012) Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res 18:4682–4690PubMedGoogle Scholar
  49. Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM et al (2015) RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med 21:1038–1047PubMedPubMedCentralGoogle Scholar
  50. Huang Q, Schneeberger VE, Luetteke N, Jin C, Afzal R, Budzevich MM et al (2016) Preclinical modeling of KIF5B-RET fusion lung adenocarcinoma. Mol Cancer Ther 15(10):2521–2529PubMedPubMedCentralGoogle Scholar
  51. Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J et al (2006) Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 66:7854–7858Google Scholar
  52. Isozaki H, Ichihara E, Takigawa N, Ohashi K, Ochi N, Yasugi M et al (2016) Non-small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases. Cancer Res 76:1506–1516PubMedGoogle Scholar
  53. Jänne PA, Yang JC-H, Kim D-W, Planchard D, Ohe Y, Ramalingam SS et al (2015) AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689–1699PubMedGoogle Scholar
  54. Jia Y, Yun C-H, Park E, Ercan D, Manuia M, Juarez J et al (2016) Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534:129–132PubMedPubMedCentralGoogle Scholar
  55. Kang CW, Jang KW, Sohn J, Kim S-M, Pyo K-H, Kim H et al (2015) Antitumor activity and acquired resistance mechanism of dovitinib (TKI258) in RET-rearranged lung adenocarcinoma. Mol Cancer Ther 14:2238–2248PubMedGoogle Scholar
  56. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B et al (2012) Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 4:120ra17PubMedPubMedCentralGoogle Scholar
  57. Katayama R, Friboulet L, Koike S, Lockerman EL, Khan TM, Gainor JF et al (2014) Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res 20:5686–5696PubMedPubMedCentralGoogle Scholar
  58. Katayama R, Kobayashi Y, Friboulet L, Lockerman EL, Koike S, Shaw AT et al (2015) Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer. Clin Cancer Res 21:166–174PubMedGoogle Scholar
  59. Khalifa J, Amini A, Popat S, Gaspar LE, Faivre-Finn C (2016) Brain metastases from NSCLC: radiation therapy in the era of targeted therapies. J Thorac Oncol 11:1627–1643PubMedGoogle Scholar
  60. Kim S, Kim TM, Kim D-W, Go H, Keam B, Lee S-H et al (2013) Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol 8:415–422PubMedGoogle Scholar
  61. Kim TM, Song A, Kim D-W, Kim S, Ahn Y-O, Keam B et al (2015) Mechanisms of acquired resistance to AZD9291, a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol 10:1736–1744PubMedGoogle Scholar
  62. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M et al (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792PubMedGoogle Scholar
  63. Kobayashi Y, Sakao Y, Ito S, Sakakura N, Usami N, Mitsudomi T et al (2013) Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies. J Thorac Oncol 8:75–78Google Scholar
  64. Kogita A, Togashi Y, Hayashi H, Sogabe S, Terashima M, De Velasco MA et al (2014) Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition. Int J Oncol 45:1430–1436PubMedPubMedCentralGoogle Scholar
  65. Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T et al (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med 18:375–357PubMedGoogle Scholar
  66. Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703PubMedPubMedCentralGoogle Scholar
  67. Lin JJ, Kennedy E, Sequist LV, Brastianos PK, Goodwin KE, Stevens S et al (2016) Clinical activity of alectinib in advanced RET-rearranged non-small-cell lung cancer. J Thorac Oncol 11:2027–2032PubMedGoogle Scholar
  68. Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y et al (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027–1034PubMedPubMedCentralGoogle Scholar
  69. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW 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 350:2129–2139PubMedPubMedCentralGoogle Scholar
  70. Mao C, Yuan J-Q, Yang Z-Y, Fu X-H, Wu X-Y, Tang J-L (2015) Blood as a substitute for tumor tissue in detecting EGFR mutations for guiding EGFR TKIs treatment of nonsmall cell lung cancer: a systematic review and meta-analysis. Medicine (Baltimore) 94:e775Google Scholar
  71. McCoach CE, Le AT, Aisner D, Gowan K, Jones KL, Merrick D et al (2016) Resistance mechanisms to targeted therapies in ROS1+ and ALK+ non-small cell lung cancer. J Clin Oncol 34:(suppl; abstr 9065)Google Scholar
  72. Mengoli MC, Barbieri F, Bertolini F, Tiseo M, Rossi G (2016) K-RAS mutations indicating primary resistance to crizotinib in ALK-rearranged adenocarcinomas of the lung: report of two cases and review of the literature. Lung Cancer 93:55–58PubMedGoogle Scholar
  73. Minari R, Bordi P, Tiseo M (2016) Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance. Transl Lung Cancer Res 5:695–708PubMedPubMedCentralGoogle Scholar
  74. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957PubMedGoogle Scholar
  75. Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS et al (2016) Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med [Epub ahead of print]Google Scholar
  76. Nguyen K-SH, Kobayashi S, Costa DB (2009) 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 10:281–289PubMedPubMedCentralGoogle Scholar
  77. Nguyen-Ngoc T, Bouchaab H, Adjei AA, Peters S (2015) BRAF alterations as therapeutic targets in non-small cell lung cancer. J Thorac Oncol 10:1396–1403PubMedGoogle Scholar
  78. Niederst MJ, Engelman JA (2013) Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal 6:re6PubMedGoogle Scholar
  79. Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR et al (2015a) RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 6:6377PubMedPubMedCentralGoogle Scholar
  80. Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR, Piotrowska Z et al (2015b) The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin Cancer Res 21:3924–3933PubMedPubMedCentralGoogle Scholar
  81. Noeparast A, Teugels E, Giron P, Verschelden G, De Brakeleer S, Decoster L et al (2016) Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of trametinib and dabrafenib. Oncotarget [Epub ahead of print]Google Scholar
  82. Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG et al (2016) Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 27:v1–27PubMedGoogle Scholar
  83. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL et al (2012) Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A 109:E2127–E2133PubMedPubMedCentralGoogle Scholar
  84. Omachi N, Shimizu S, Kawaguchi T, Tezuka K, Kanazu M, Tamiya A et al (2014) A case of large-cell neuroendocrine carcinoma harboring an EML4-ALK rearrangement with resistance to the ALK inhibitor crizotinib. J Thorac Oncol 9:e40–e42PubMedGoogle Scholar
  85. Ortiz-Cuaran S, Scheffler M, Plenker D, Dahmen L, Scheel AH, Fernandez-Cuesta L et al (2016) Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res 22:4837–4847PubMedGoogle Scholar
  86. Oser MG, Niederst MJ, Sequist LV, Engelman JA (2015) Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol 16:e165–e172PubMedPubMedCentralGoogle Scholar
  87. Ou S-HI, Tan J, Yen Y, Soo RA (2012) ROS1 as a “druggable” receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway. Expert Rev Anticancer Ther 12:447–456PubMedGoogle Scholar
  88. Ou SHI, Agarwal N, Ali SM (2016a) High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer 98:59–61PubMedGoogle Scholar
  89. Ou S-HI, Young L, Schrock AB, Johnson A, Klempner SJ, Zhu VW et al (2016b) Emergence of pre-existing MET Y1230C mutation as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol 12:137–140PubMedGoogle Scholar
  90. Oxnard GR, Thress K, Paweletz CP, Stetson D, Dougherty B, Lai Z et al (2015) Mechanisms of acquired resistance to AZD9291 in EGFRT790M positive lung cancer. J Thorac Oncol 9(suppl 2):S207Google Scholar
  91. Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M et al (2016) Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 34:3375–3382PubMedPubMedCentralGoogle Scholar
  92. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500Google Scholar
  93. Park K, Yu C-J, Kim S-W, Lin M-C, Sriuranpong V, Tsai C-M et al (2016) First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION study. JAMA Oncol 2:305–312PubMedGoogle Scholar
  94. Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M et al (2015) Heterogeneity underlies the emergence of EGFRT790wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov 5:713–723PubMedPubMedCentralGoogle Scholar
  95. Planchard D, Loriot Y, André F, Gobert A, Auger N, Lacroix L et al (2015) EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol 26:2073–2208PubMedGoogle Scholar
  96. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F et al (2016a) Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 17:642–650PubMedPubMedCentralGoogle Scholar
  97. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS et al (2016b) Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 17:984–993PubMedPubMedCentralGoogle Scholar
  98. Reckamp KL, Melnikova VO, Karlovich C, Sequist LV, Camidge DR, Wakelee H et al (2016) A highly sensitive and quantitative test platform for detection of NSCLC EGFR mutations in urine and plasma. J Thorac Oncol 11:1690–1700PubMedGoogle Scholar
  99. Redaelli S, Ceccon M, Antolini L, Rigolio R, Pirola A, Peronaci M et al (2016) Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma. Oncotarget 7:72886–72897PubMedPubMedCentralGoogle Scholar
  100. Remon J, Caramella C, Jovelet C, Lacroix L, Lawson A, Smalley S et al (2017) Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA. Ann Oncol [Epub ahead of print]Google Scholar
  101. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967PubMedGoogle Scholar
  102. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E 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 13:239–246PubMedGoogle Scholar
  103. Rudin CM, 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–e42PubMedPubMedCentralGoogle Scholar
  104. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551PubMedGoogle Scholar
  105. Schmid S, Gautschi O, Rothschild S, Mark M, Froesch P, Klingbiel D et al (2016) Clinical outcome of ALK-positive non-small cell lung cancer (NSCLC) patients with de novo EGFR or KRAS co-mutations receiving tyrosine kinase inhibitors (TKI). J Thorac Oncol [Epub ahead of print]Google Scholar
  106. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26PubMedPubMedCentralGoogle Scholar
  107. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A et al (2015) Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 372:1700–1709PubMedGoogle Scholar
  108. Sequist LV, Piotrowska Z, Niederst MJ, Heist RS, Digumarthy S, Shaw AT et al (2016) Osimertinib responses after disease progression in patients who had been receiving rociletinib. JAMA Oncol 2:541–543PubMedGoogle Scholar
  109. Shaw AT, Kim D-W, Mehra R, Tan DSW, Felip E, Chow LQM et al (2014) Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med 370:1189–1197PubMedPubMedCentralGoogle Scholar
  110. Shaw AT, Friboulet L, Leshchiner I, Gainor JF, Bergqvist S, Brooun A et al (2015) Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N Engl J Med 374:54–61PubMedPubMedCentralGoogle Scholar
  111. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics 2016. CA Cancer J Clin 66:7–30PubMedGoogle Scholar
  112. Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T et al (2014) First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167–2177PubMedGoogle Scholar
  113. Song A, Kim TM, Kim D-W, Kim S, Keam B, Lee S-H et al (2015) Molecular changes associated with acquired resistance to crizotinib in ROS1-rearranged non-small cell lung cancer. Clin Cancer Res 21:2379–2387PubMedGoogle Scholar
  114. Soo R, Kim D-W, Yang JC-H, Park K, Stammberger U, Xiong H et al (2015) Highly selective c-Met inhibitor tepotinib plus gefitinib is active in Asian patients with c-Met+ NSCLC. Ann Oncol 26(suppl 9):ix143Google Scholar
  115. Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ et al (2015) Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 16:990–998PubMedGoogle Scholar
  116. Soria JC, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ et al (2016) Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC after progression on 1st line gefitinib (IMPRESS study): final overall survival (OS) analysis. Ann Oncol 27(suppl 6):1201OGoogle Scholar
  117. Su KY, Chen HY, Li KC, Kuo ML, Yang JCH, Chan WK et al (2012) Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 30:433–440PubMedGoogle Scholar
  118. Suda K, Murakami I, Sakai K, Tomizawa K, Mizuuchi H, Sato K et al (2016) Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer. Lung Cancer 91:36–40PubMedGoogle Scholar
  119. Suda K, Bunn PA, Rivard CJ, Mitsudomi T, Hirsch FR (2017) Primary double-strike therapy for cancers to overcome EGFR kinase inhibitor resistance: proposal from the bench. J Thorac Oncol 12:27–35PubMedGoogle Scholar
  120. Sundaresan TK, Sequist LV, Heymach JV, Riely GJ, Jänne PA, Koch WH et al (2016) Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res 22:1103–1110PubMedGoogle Scholar
  121. Takegawa N, Hayashi H, Iizuka N, Takahama T, Ueda H, Tanaka K et al (2016) Transformation of ALK rearrangement-positive adenocarcinoma to small-cell lung cancer in association with acquired resistance to alectinib. Ann Oncol 27:953–955PubMedGoogle Scholar
  122. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E et al (2012) HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFR T790M mutation. Cancer Discov 2:922–933PubMedPubMedCentralGoogle Scholar
  123. Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N et al (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65:9455–9462PubMedGoogle Scholar
  124. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B et al (2015) Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 21:560–562PubMedPubMedCentralGoogle Scholar
  125. Toyokawa G, Inamasu E, Shimamatsu S, Yoshida T, Nosaki K, Hirai F et al (2015) Identification of a novel ALK G1123S mutation in a patient with ALK-rearranged non-small-cell lung cancer exhibiting resistance to ceritinib. J Thorac Oncol 10:e55–e57PubMedGoogle Scholar
  126. Tricker EM, Xu C, Uddin S, Capelletti M, Ercan D, Ogino A et al (2015) Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer. Cancer Discov 5:960–971PubMedPubMedCentralGoogle Scholar
  127. Tseng JS, Yang TY, Tsai CR, Chen KC, Hsu KH, Tsai MH et al (2015) Dynamic plasma EGFR mutation status as a predictor of EGFR-TKI efficacy in patients with EGFR-mutant lung adenocarcinoma. J Thorac Oncol 10:603–610PubMedGoogle Scholar
  128. Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E et al (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17:77–88PubMedPubMedCentralGoogle Scholar
  129. Ulivi P, Chiadini E, Dazzi C, Dubini A, Costantini M, Medri L et al (2016) Nonsquamous, non-small-cell lung cancer patients who carry a double mutation of EGFR, EML4-ALK or KRAS: frequency, clinical-pathological characteristics, and response to therapy. Clin Lung Cancer 17:384–390PubMedGoogle Scholar
  130. Wang L, Hu H, Pan Y, Wang R, Li Y, Shen L et al (2014) PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup. PLoS One 9:e0088291Google Scholar
  131. Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA et al (2012) Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 7:1807–1814PubMedPubMedCentralGoogle Scholar
  132. Woo CG, Seo S, Kim SW, Jang SJ, Park KS, Song JY et al (2016) Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Ann Oncol [Epub ahead of print]Google Scholar
  133. Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC (2011) Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 17:3812–3821PubMedGoogle Scholar
  134. Wu H, Shih JY, Yang JC (2015) Rapid response to sunitinib in a patient with lung adenocarcinoma harboring KIF5B-RET fusion gene. J Thorac Oncol 10:e95–e96PubMedGoogle Scholar
  135. Wu YL, Kim DW, Felip E, Zhang L, Liu X, Zhou CC et al (2016) Phase (Ph) II safety and efficacy results of a single-arm ph ib/II study of capmatinib (INC280) + gefitinib in patients (pts) with EGFR-mutated (mut), cMET-positive (cMET + ) non-small cell lung cancer (NSCLC). J Clin Oncol 34:(suppl;abstr 9020)Google Scholar
  136. Yang JCH, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N et al (2015) Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-lung 3 and LUX-lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 16:141–151PubMedGoogle Scholar
  137. Yang J, Ramalingam SS, Jänne PA, Cantarini M, Mitsudomi T (2016) Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated phase 1 (P1) and pooled phase 2 (P2) results. J Thorac Oncol 11(suppl 4):S152–S153Google Scholar
  138. Yap TA, Macklin-Doherty A, Popat S (2017) Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer. Eur J Cancer 70:12–21PubMedGoogle Scholar
  139. Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL et al (2013) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 5:216ra177PubMedPubMedCentralGoogle Scholar
  140. Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H et al (2017) Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med 5:42–50PubMedGoogle Scholar
  141. Yoshida T, Oya Y, Tanaka K, Shimizu J, Horio Y, Kuroda H et al (2016) Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer. J Clin Oncol 34:3383–3389PubMedGoogle Scholar
  142. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W et al (2013a) 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 19:2240–2247PubMedPubMedCentralGoogle Scholar
  143. Yu HA, Sima CS, Huang J, Solomon SB, Rimner A, Paik P et al (2013b) Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 8:346–351PubMedPubMedCentralGoogle Scholar
  144. Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T et al (2012) Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 44:852–860PubMedPubMedCentralGoogle Scholar
  145. Zou H, Friboulet L, Kodack D, Engstrom L, Li Q, West M et al (2015) PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical odels. Cancer Cell 28:70–81PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Francesco Facchinetti
    • 1
  • Claudia Proto
    • 2
  • Roberta Minari
    • 1
  • Marina Garassino
    • 2
  • Marcello Tiseo
    • 1
    Email author
  1. 1.Medical Oncology UnitUniversity Hospital of ParmaParmaItaly
  2. 2.Thoracic Oncology Unit, Department of Medical Oncology 1Fondazione IRCCS, Istituto Nazionale dei TumoriMilanItaly

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