Abstract
Drug resistance is a major factor that limits the efficacy of targeted cancer therapies. In this review, we discuss the main known mechanisms of resistance to receptor tyrosine kinase inhibitors, which are the most prevalent class of targeted therapeutic agent in current clinical use. Here we focus on bypass track resistance, which involves the activation of alternate signaling molecules by tumor cells to bypass inhibition and maintain signaling output, and consider the problems of signaling pathway redundancy and how the activation of different receptor tyrosine kinases translates into intracellular signal transduction in different cancer types. This information is presented in the context of research strategies for the discovery of new targets for pharmacological intervention, with the goal of overcoming resistance in order to improve patient outcomes.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Weinstein IB, Joe A, Felsher D. Oncogene addiction. Cancer Res 2008; 68(9): 3077–3080, discussion 3080
Sawyers C. Targeted cancer therapy. Nature 2004; 432(7015): 294–297
Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010; 141(7): 1117–1134
Chong CR, Jänne PA. The quest to overcome resistance to EGFRtargeted therapies in cancer. Nat Med 2013; 19(11): 1389–1400
Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013; 13(10): 714–726
Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol 2013; 31(31): 3987–3996
Groenendijk FH, Bernards R. Drug resistance to targeted therapies: déjà vu all over again. Mol Oncol 2014; 8(6): 1067–1083
Sun C, Bernards R. Feedback and redundancy in receptor tyrosine kinase signaling: relevance to cancer therapies. Trends Biochem Sci 2014; 39(10): 465–474
Ercan D, Zejnullahu K, Yonesaka K, Xiao Y, Capelletti M, Rogers A, Lifshits E, Brown A, Lee C, Christensen JG, Kwiatkowski DJ, Engelman JA, Jänne PA. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 2010; 29(16): 2346–2356
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3(75): 75ra26
Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, Drew L, Saeh JC, Crosby K, Sequist LV, Iafrate AJ, Engelman JA. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 2012; 4(120): 120ra17
Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18(5): 1472–1482
Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 2008; 105(6): 2070–2075
Niederst MJ, Engelman JA. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal 2013; 6(294): re6
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316(5827): 1039–1043
Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007; 104(52): 20932–20937
Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001; 93(24): 1852–1857
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487(7408): 505–509
Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, Lindeman NI, Murphy C, Akhavanfard S, Yeap BY, Xiao Y, Capelletti M, Iafrate AJ, Lee C, Christensen JG, Engelman JA, Jänne PA. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010; 17(1): 77–88
Wagner JP, Wolf-Yadlin A, Sevecka M, Grenier JK, Root DE, Lauffenburger DA, MacBeath G. Receptor tyrosine kinases fall into distinct classes based on their inferred signaling networks. Sci Signal 2013; 6(284): ra58
Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, McDermott U, Azizian N, Zou L, Fischbach MA, Wong KK, Brandstetter K, Wittner B, Ramaswamy S, Classon M, Settleman J. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141(1): 69–80
Grueneberg DA, Degot S, Pearlberg J, Li W, Davies JE, Baldwin A, Endege W, Doench J, Sawyer J, Hu Y, Boyce F, Xian J, Munger K, Harlow E. Kinase requirements in human cells: I. Comparing kinase requirements across various cell types. Proc Natl Acad Sci USA 2008; 105(43): 16472–16477
Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT, Lifshits E, Chen Z, Maira SM, García-Echeverría C, Wong KK, Engelman JA. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci USA 2009; 106(46): 19503–19508
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483(7387): 100–103
Wang Q, Quan H, Zhao J, Xie C, Wang L, Lou L. RON confers lapatinib resistance in HER2-positive breast cancer cells. Cancer Lett 2013; 340(1): 43–50
Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, Gandhi L, Shapiro GI, Nelson JM, Heymach JV, Meyerson M, Wong KK, Jänne PA. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007; 67(24): 11924–11932
Alexander PB, Yuan L, Yang P, Sun T, Chen R, Xiang H, Chen J, Wu H, Radiloff DR, Wang XF. EGF promotes mammalian cell growth by suppressing cellular senescence. Cell Res 2015; 25(1): 135–138
Lee HJ, Schaefer G, Heffron TP, Shao L, Ye X, Sideris S, Malek S, Chan E, Merchant M, La H, Ubhayakar S, Yauch RL, Pirazzoli V, Politi K, Settleman J. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov 2013; 3(2): 168–181
Kummar S, Chen HX, Wright J, Holbeck S, Millin MD, Tomaszewski J, Zweibel J, Collins J, Doroshow JH. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat Rev Drug Discov 2010; 9(11): 843–856
Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, Frias RL, Gainor JF, Amzallag A, Greninger P, Lee D, Kalsy A, Gomez-Caraballo M, Elamine L, Howe E, Hur W, Lifshits E, Robinson HE, Katayama R, Faber AC, Awad MM, Ramaswamy S, Mino-Kenudson M, Iafrate AJ, Benes CH, Engelman JA. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 2014; 346(6216): 1480–1486
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Alexander, P.B., Wang, XF. Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies. Front. Med. 9, 134–138 (2015). https://doi.org/10.1007/s11684-015-0396-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11684-015-0396-9