Advances in genomics, an improved understanding of malignant transformation, and the development of potent small molecule inhibitors capable of targeting key kinases have led to the adoption of genotype-guided approaches for the treatment of advanced cancers. As regulators of complex signaling networks, tyrosine kinases are among the most attractive targets. Moreover, insight into the conserved three-dimensional structures of these kinases and their mechanism of activation has facilitated the development of selective tyrosine kinase inhibitors (TKIs). TKIs have shown robust clinical activity in many different oncogene-addicted cancers; however, resistance invariably develops. In a significant proportion of patients, resistance results from acquired genetic alterations within the kinase target that allow cancer cells to escape TKI-mediated growth suppression. In this review, we discuss clinically observed and preclinical on-target resistance events in oncogene-driven solid tumors and describe current and future therapeutic strategies to overcome this type of resistance.


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Literature Cited

  1. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G. et al. 2005. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin. Cancer Res. 11:4182–90 [Google Scholar]
  2. Awad MM, Katayama R, McTigue M, Liu W, Deng YL. et al. 2013. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N. Engl. J. Med. 368:2395–401 [Google Scholar]
  3. Bai RY, Ouyang T, Miething C, Morris SW, Peschel C, Duyster J. 2000. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 96:4319–27 [Google Scholar]
  4. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM. et al. 2012. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. 30:863–70 [Google Scholar]
  5. Bersanelli M, Minari R, Bordi P, Gnetti L, Bozzetti C. et al. 2016. L718Q mutation as new mechanism of acquired resistance to AZD9291 in EGFR-mutated NSCLC. J. Thorac. Oncol. 11:e121–23 [Google Scholar]
  6. Bhang HE, Ruddy DA, Krishnamurthy V, Caushi JX, Zhao R. et al. 2015. Studying clonal dynamics in response to cancer therapy using high complexity barcoding. Nat. Med. 21:440–48 [Google Scholar]
  7. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B. et al. 2008. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J. Clin. Oncol. 26:620–25 [Google Scholar]
  8. Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K. et al. 2014. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 26:682–94 [Google Scholar]
  9. Butrynski JE, D'Adamo DR, Hornick JL, Dal Cin P, Antonsecu CR. et al. 2010. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N. Engl. J. Med. 363:1727–33 [Google Scholar]
  10. Chao MV. 2003. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat. Rev. Neurosci. 4:299–309 [Google Scholar]
  11. Chen LL, Trent JC, Wu EF, Fuller GN, Ramdas L. et al. 2004. A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 64:5913–19 [Google Scholar]
  12. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. 2008. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat. Rev. Cancer 8:11–23 [Google Scholar]
  13. Chmielecki J, Foo J, Oxnard GR, Hutchinson K, Ohashi K. et al. 2011. Optimization of dosing for EGFR-mutant non–small cell lung cancer with evolutionary cancer modeling. Sci. Transl. Med. 3:90ra59 [Google Scholar]
  14. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J. et al. 2010. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N. Engl. J. Med. 363:1734–39 [Google Scholar]
  15. Davare MA, Vellore NA, Wagner JP, Eide CA, Goodman JR. et al. 2015. Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors. PNAS 112:E5381–90 [Google Scholar]
  16. Davies KD, Doebele RC. 2013. Molecular pathways: ROS1 fusion proteins in cancer. Clin. Cancer Res. 19:4040–45 [Google Scholar]
  17. Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL. et al. 2012. Identifying and targeting ROS1 gene fusions in non–small cell lung cancer. Clin. Cancer Res. 18:4570–79 [Google Scholar]
  18. Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A. et al. 2015. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov 5:1049–57 [Google Scholar]
  19. Doebele RC, Pilling AB, Aisner DL, Katateladze TG, Le AT. et al. 2012. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non–small cell lung cancer. Clin. Cancer Res. 18:1472–82 [Google Scholar]
  20. Drake J, Lee JK, Witte ON. 2014. Clinical targeting of mutated and wild-type protein tyrosine kinases in cancer. Mol. Cell. Biol. 34:1722–32 [Google Scholar]
  21. Drilon A, Li G, Dogan S, Gounder M, Shen R. et al. 2016a. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann. Oncol. 27:920–26 [Google Scholar]
  22. Drilon A, Somwar R, Wagner JP, Vellore NA, Eide CA. et al. 2016b. A novel crizotinib-resistance solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin. Cancer Res. 22:2351–58 [Google Scholar]
  23. Ercan D, Choi HG, Yun CH, Capelleti M, Xie T. et al. 2015. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin. Cancer Res. 21:3913–23 [Google Scholar]
  24. Ercan D, Zejnullahu K, Yonesaka K, Xiao Y, Capelleti M. et al. 2010. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 29:2346–56 [Google Scholar]
  25. Facchinetti F, Loriot Y, Cassin-Kuo MS, Mahjoubi L, Lacroix L. et al. 2016. Crizotinib-resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1- and ALK-rearranged lung cancers. Clin Cancer Res. In press [Google Scholar]
  26. Farago AF, Le LP, Zheng Z, Muzikansky A, Drilon A. et al. 2015. Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer. J. Thorac. Oncol. 10:1670–74 [Google Scholar]
  27. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF. et al. 2014. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 4:662–73 [Google Scholar]
  28. Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I. et al. 2016. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 6:1118–33 [Google Scholar]
  29. Gambacorti-Passerini C, Mussolin L, Brugieres L. 2016. Abrupt relapse of ALK-positive lymphoma after discontinuation of crizotinib. N. Engl. J. Med. 374:95–96 [Google Scholar]
  30. Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:646–74 [Google Scholar]
  31. Hata A, Katakami N, Yoshioka H, Kaji R, Masago K. 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. 10:1553–59 [Google Scholar]
  32. Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM. et al. 2016. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22:262–69 [Google Scholar]
  33. Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S. et al. 2015. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat. Med. 21:1038–47 [Google Scholar]
  34. Hynes NE, Lane HA. 2005. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer 5:341–54 [Google Scholar]
  35. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y. et al. 2015. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372:1689–99 [Google Scholar]
  36. Ji JH, Oh YL, Hong M, Yun JW, Lee HW. et al. 2015. Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer. PLOS Genet 11:e1005467 [Google Scholar]
  37. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C. et al. 2002. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346:645–52 [Google Scholar]
  38. Katayama R, Friboulet L, Koike S, Lockerman EL, Khan TM. et al. 2014. Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin. Cancer Res. 20:5686–96 [Google Scholar]
  39. Katayama R, Kobayashi Y, Friboulet L, Lockerman EL, Koike S. et al. 2015. Cabozantinib overcomes crizotinib resistance in ROS1 fusion–positive cancer. Clin. Cancer Res. 21:166–74 [Google Scholar]
  40. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ. et al. 2012. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci. Transl. Med. 4:120ra17 [Google Scholar]
  41. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O. et al. 2005. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352:786–92 [Google Scholar]
  42. Kodityal S, Elvin JA, Squillace R, Agarwal N, Miller VA. et al. 2016. A novel acquired ALK F1245C mutation confers resistance to crizotinib in ALK-positive NSCLC but is sensitive to ceritinib. Lung Cancer 92:19–21 [Google Scholar]
  43. Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ. et al. 2014. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998–2006 [Google Scholar]
  44. Kris MG, Natale RB, Herbst RS, Lynch TJ, Prager D. et al. 2003. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–58 [Google Scholar]
  45. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B. et al. 2010. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363:1693–703 [Google Scholar]
  46. Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P. et al. 2000. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am. J. Pathol. 157:377–84 [Google Scholar]
  47. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F. et al. 2014. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 371:1877–88 [Google Scholar]
  48. Luo J, Solimini NL, Elledge SJ. 2009. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–37 [Google Scholar]
  49. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA. 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. 350:2129–39 [Google Scholar]
  50. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B. et al. 2008. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359:366–77 [Google Scholar]
  51. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. 2002. The protein kinase complement of the human genome. Science 298:1912–34 [Google Scholar]
  52. Matsushime H, Wang LH, Shibuya M. 1986. Human c-ros-1 gene homologous to the v-ros sequence of UR2 sarcoma virus encodes for a transmembrane receptorlike molecule. Mol. Cell. Biol. 6:3000–4 [Google Scholar]
  53. McCoach CE, Le AT, Aisner DL, Gowan K, Jones KL. et al. 2016. Resistance mechanisms to targeted therapy in ROS1+ and ALK+ non-small cell lung cancer. J. Clin. Oncol. 34:Suppl.9065 Abstr. [Google Scholar]
  54. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT. et al. 2009. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinooma. N. Engl. J. Med. 361:947–57 [Google Scholar]
  55. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN. et al. 1994. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263:1281–84 [Google Scholar]
  56. Niederst MJ, Hu H, Mulvey HE, Lockerman EL, Garcia AR. et al. 2015. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin. Cancer Res. 21:3924–33 [Google Scholar]
  57. Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC. et al. 2016. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J. Clin. Oncol. 34:661–68 [Google Scholar]
  58. Ou SH, Azada M, Hsiang DJ, Herman JM, Kain TS. et al. 2014a. Next-generation sequencing reveals a novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib in ALK-rearranged NSCLC patients who progressed on crizotinib. J. Thorac. Oncol. 9:549–53 [Google Scholar]
  59. Ou SH, Klempner SJ, Greenbowe JR, Azada M, Schrock AB. et al. 2014b. Identification of a novel HIP1-ALK fusion variant in non-small-cell lung cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to alectinib. J. Thorac. Oncol. 9:1821–25 [Google Scholar]
  60. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H. et al. 2004. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–500 [Google Scholar]
  61. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R. et al. 2005. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLOS Med 2:e73 [Google Scholar]
  62. Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW. et al. 2015. Heterogeneity underlies the emergence of EGFR T790 wild-type clones following treatment of T790M-positive cancers with a third generation EGFR inhibitor. Cancer Discov 5:713–22 [Google Scholar]
  63. Pirazzoli V, Aveni D, Meador CB, Sanganahalli BG, Hyder F. et al. 2016. Afatinib plus cetuximab delays resistance compared to single-agent erlotinib or afatinib in mouse models of TKI-naive EGFR L858R-induced lung adenocarcinoma. Clin. Cancer Res. 22:426–35 [Google Scholar]
  64. Ramirez M, Rajaram S, Steininger RJ, Osipchuk D, Roth MA. et al. 2016. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 7:10690 [Google Scholar]
  65. Rikova K, Guo A, Zeng Q, Possemato A, Yu J. et al. 2007. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–203 [Google Scholar]
  66. Rimkunas VM, Crosby KE, Hu Y, Kelly ME. et al. 2012. Analysis of receptor tyrosine kinase ROS1-positive tumors in non–small cell lung cancer: identification of a FIG-ROS1 fusion. Clin. Cancer Res. 18:4449–57 [Google Scholar]
  67. Robinson DR, Wu YM, Lin SF. 2000. The protein tyrosine kinase family of the human genome. Oncogene 19:5548–57 [Google Scholar]
  68. Rosell R, Carcereny E, Gervais R, Vergnegre A, Massuti B. 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 13:239–46 [Google Scholar]
  69. Russo M, Misale S, Wei G, Siravegna G, Crisafulli G. et al. 2016. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov 6:36–44 [Google Scholar]
  70. Sasaki T, Koivunen J, Ogino A, Yanagita M, Nikiforow S. et al. 2011. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 71:6051–60 [Google Scholar]
  71. Schottle J, Chatterjee S, Volz C, Siobal M, Florin A. et al. 2015. Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer. Oncotarget 6:38458–68 [Google Scholar]
  72. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM. et al. 2015. Rociletinib in EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 372:1700–9 [Google Scholar]
  73. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB. et al. 2011. Genotypic and histologic evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3:75ra26 [Google Scholar]
  74. Sharma SV, Settleman J. 2007. Oncogene addiction: setting the stage for molecular targeted cancer therapy. Genes Dev 21:3214–31 [Google Scholar]
  75. Shaw AT, Friboulet L, Leshchiner I, Gainor JF, Bergqvist S. et al. 2016a. Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N. Engl. J. Med. 374:54–61 [Google Scholar]
  76. Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J. et al. 2016b. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 17:234–42 [Google Scholar]
  77. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E. et al. 2014. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370:1189–97 [Google Scholar]
  78. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L. et al. 2013. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368:2385–94 [Google Scholar]
  79. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ. et al. 2011a. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371:1963–71 [Google Scholar]
  80. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB. et al. 2009. Clinical features and outcomes of patients with non-small-cell lung cancer who harbor EML4-ALK. J. Clin. Oncol. 27:4247–53 [Google Scholar]
  81. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J. et al. 2011b. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12:1004–12 [Google Scholar]
  82. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M. et al. 2011. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365:1273–83 [Google Scholar]
  83. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y. et al. 2007. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–66 [Google Scholar]
  84. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K. et al. 2014. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371:2167–77 [Google Scholar]
  85. Su KY, Chen HY, Li KC, Kuo ML, Yang JC. 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. 30:433–40 [Google Scholar]
  86. Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S. et al. 2012. Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method. Cancer 118:4427–36 [Google Scholar]
  87. Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y. et al. 2008. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin. Cancer Res. 14:6618–24 [Google Scholar]
  88. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S. et al. 2012. RET, ROS1 and ALK fusions in lung cancer. Nat. Med. 18:378–81 [Google Scholar]
  89. Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D. et al. 2015. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nat. Med. 21:560–62 [Google Scholar]
  90. Toyokawa G, Hirai F, Inamasu E, Yashida T, Nosaki K. et al. 2014. Secondary mutations at I1171 in the ALK gene confer resistance to both crizotinib and alectinib. J. Thorac. Oncol. 9:e86–87 [Google Scholar]
  91. Tong M, Seeliger MA. 2015. Targeting conformational plasticity of protein kinases. ACS Chem. Biol. 10:190–200 [Google Scholar]
  92. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR. et al. 2009. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360:1408–17 [Google Scholar]
  93. Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M. et al. 2013. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat. Med. 19:1469–72 [Google Scholar]
  94. Vaishnavi A, Le AT, Doebele RC. 2015. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 5:25–34 [Google Scholar]
  95. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. 2013. Cancer genome landscapes. Science 339:1546–58 [Google Scholar]
  96. Walsh DA, Perkins JP, Krebs EG. 1968. An adenosine 3,5-monophosphate-dependent protein kinase from rabbit skeletal muscle. J. Biol. Chem. 243:3763–65 [Google Scholar]
  97. Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU. et al. 2006. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin. Cancer Res. 12:1743–49 [Google Scholar]
  98. Weinstein IB. 2002. Cancer addiction to oncogenes—the Achilles’ heal of cancer. Science 297:63–64 [Google Scholar]
  99. Wu P, Nielsen TE, Clausen MH. 2015. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 36:422–39 [Google Scholar]
  100. Wu SG, Liu YN, Tsai MF, Chang YL, Yu CJ. et al. 2016. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget 7:12404–13 [Google Scholar]
  101. Wylie A, Schoepfer J, Berellini G, Cai H, Caravatti G. et al. 2014. ABL001, a potent allosteric inhibitor of BCR-ABL, prevents emergence of resistant disease when administered in combination with nilotinib in an in vivo murine model of chronic myeloid leukemia. Blood 124:398 [Google Scholar]
  102. Ying J, Lin C, Wu J, Guo L, Qiu T. et al. 2015. Anaplastic lymphoma kinase rearrangement in digestive tract cancer: implications for targeted therapy in Chinese population. PLOS ONE 10:e0144731 [Google Scholar]
  103. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF. et al. 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. 19:2240–47 [Google Scholar]
  104. Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ. et al. 2015. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol 1:982–84 [Google Scholar]
  105. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H. et al. 2008. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. PNAS 105:2070–75 [Google Scholar]
  106. Zamo A, Chiarle R, Piva R, Howes J, Fan Y. et al. 2002. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene 21:1038–47 [Google Scholar]
  107. Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG. et al. 2010. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463:501–6 [Google Scholar]
  108. Zhou C, Wu YL, Chen G, Feng J, Liu XQ. et al. 2011. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL): a multicentre, open-label, randomised, phase 2 study. Lancet Oncol 12:735–42 [Google Scholar]
  109. Zhou W, Ercan D, Chen L, Yun CH, Li D. et al. 2009. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462:1070–74 [Google Scholar]
  110. Zou HY, Friboulet L, Kodack DP, Engstrom LD, Li Q. et al. 2015a. PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell 28:70–81 [Google Scholar]
  111. Zou HY, Li Q, Engstrom LD, West M, Appleman V. et al. 2015b. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. PNAS 112:3493–98 [Google Scholar]

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