Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (2) : 134-138    https://doi.org/10.1007/s11684-015-0396-9
REVIEW
Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies
Peter B. Alexander,Xiao-Fan Wang()
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
 Download: PDF(130 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
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.

Keywords targeted therapy      drug resistance      receptor tyrosine kinases      cancer     
Corresponding Author(s): Xiao-Fan Wang   
Just Accepted Date: 17 April 2015   Online First Date: 12 May 2015    Issue Date: 22 May 2015
 Cite this article:   
Peter B. Alexander,Xiao-Fan Wang. Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies[J]. Front. Med., 2015, 9(2): 134-138.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0396-9
https://academic.hep.com.cn/fmd/EN/Y2015/V9/I2/134
Fig.1  Summary of RTKs known to mediate bypass resistance to RTK targeted cancer therapy. Ovals indicate oncogenes responsible for initial tumor formation and rectangles indicate RTKs involved in drug resistance. Arrows denote known bypass resistance mechanisms. Note that EGFR and HER2 activation can induce initial tumor formation and also mediate resistance.
1 Weinstein IB, Joe A, Felsher D. Oncogene addiction. Cancer Res 2008; 68(9): 3077-3080, discussion 3080
https://doi.org/10.1158/0008-5472.CAN-07-3293 pmid: 18451130
2 Sawyers C. Targeted cancer therapy. Nature 2004; 432(7015): 294-297
https://doi.org/10.1038/nature03095 pmid: 15549090
3 Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010; 141(7): 1117-1134
https://doi.org/10.1016/j.cell.2010.06.011 pmid: 20602996
4 Chong CR, J?nne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 2013; 19(11): 1389-1400
https://doi.org/10.1038/nm.3388 pmid: 24202392
5 Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013; 13(10): 714-726
https://doi.org/10.1038/nrc3599 pmid: 24060863
6 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
https://doi.org/10.1200/JCO.2012.45.2029 pmid: 24101047
7 Groenendijk FH, Bernards R. Drug resistance to targeted therapies: déjà vu all over again. Mol Oncol 2014; 8(6): 1067-1083
https://doi.org/10.1016/j.molonc.2014.05.004 pmid: 24910388
8 Sun C, Bernards R. Feedback and redundancy in receptor tyrosine kinase signaling: relevance to cancer therapies. Trends Biochem Sci 2014; 39(10): 465-474
https://doi.org/10.1016/j.tibs.2014.08.010 pmid: 25239057
9 Ercan D, Zejnullahu K, Yonesaka K, Xiao Y, Capelletti M, Rogers A, Lifshits E, Brown A, Lee C, Christensen JG, Kwiatkowski DJ, Engelman JA, J?nne PA. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 2010; 29(16): 2346-2356
https://doi.org/10.1038/onc.2009.526 pmid: 20118985
10 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
https://doi.org/10.1126/scitranslmed.3002003 pmid: 21430269
11 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
https://doi.org/10.1126/scitranslmed.3003316 pmid: 22277784
12 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
https://doi.org/10.1158/1078-0432.CCR-11-2906 pmid: 22235099
13 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
https://doi.org/10.1073/pnas.0709662105 pmid: 18227510
14 Niederst MJ, Engelman JA. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal 2013; 6(294): re6
https://doi.org/10.1126/scisignal.2004652 pmid: 24065147
15 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, J?nne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316(5827): 1039-1043
https://doi.org/10.1126/science.1141478 pmid: 17463250
16 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
https://doi.org/10.1073/pnas.0710370104 pmid: 18093943
17 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
https://doi.org/10.1093/jnci/93.24.1852 pmid: 11752009
18 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
https://doi.org/10.1038/nature11249 pmid: 22763448
19 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, J?nne PA. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010; 17(1): 77-88
https://doi.org/10.1016/j.ccr.2009.11.022 pmid: 20129249
20 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
https://doi.org/10.1126/scisignal.2003994 pmid: 23861540
21 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
https://doi.org/10.1016/j.cell.2010.02.027 pmid: 20371346
22 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
https://doi.org/10.1073/pnas.0808019105 pmid: 18948591
23 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
https://doi.org/10.1073/pnas.0905056106 pmid: 19850869
24 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
https://doi.org/10.1038/nature10868 pmid: 22281684
25 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
https://doi.org/10.1016/j.canlet.2013.06.022 pmid: 23811285
26 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, J?nne 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
https://doi.org/10.1158/0008-5472.CAN-07-1885 pmid: 18089823
27 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
pmid: 25367123
28 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
https://doi.org/10.1158/2159-8290.CD-12-0357 pmid: 23229345
29 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
https://doi.org/10.1038/nrd3216 pmid: 21031001
30 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
https://doi.org/10.1126/science.1254721 pmid: 25394791
[1] Yong Fan, Yan Geng, Lin Shen, Zhuoli Zhang. Advances on immune-related adverse events associated with immune checkpoint inhibitors[J]. Front. Med., 2021, 15(1): 33-42.
[2] Solmaz Ohadian Moghadam, Seyed Ali Momeni. Human microbiome and prostate cancer development: current insights into the prevention and treatment[J]. Front. Med., 2021, 15(1): 11-32.
[3] Hongnan Mo, Binghe Xu. Progress in systemic therapy for triple-negative breast cancer[J]. Front. Med., 2021, 15(1): 1-10.
[4] Ching-Hon Pui. Precision medicine in acute lymphoblastic leukemia[J]. Front. Med., 2020, 14(6): 689-700.
[5] Shengfen Wang, Yang Zhou, Bing Zhao, Xichao Ou, Hui Xia, Yang Zheng, Yuanyuan Song, Qian Cheng, Xinyang Wang, Yanlin Zhao. Characteristics of compensatory mutations in the rpoC gene and their association with compensated transmission of Mycobacterium tuberculosis[J]. Front. Med., 2020, 14(1): 51-59.
[6] Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu. Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer[J]. Front. Med., 2020, 14(1): 60-67.
[7] Jiajia Hu, Wenbin Shen, Qian Qu, Xiaochun Fei, Ying Miao, Xinyun Huang, Jiajun Liu, Yingli Wu, Biao Li. NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation inhibition[J]. Front. Med., 2019, 13(6): 646-657.
[8] Rui Zhou, Yuanshu Liu, Wenjun Huang, Xitong Dang. Potential functions of esophageal cancer-related gene-4 in the cardiovascular system[J]. Front. Med., 2019, 13(6): 639-645.
[9] Hong Zhang, Ying Chang, Qingqing Zheng, Rong Zhang, Cheng Hu, Weiping Jia. Altered intestinal microbiota associated with colorectal cancer[J]. Front. Med., 2019, 13(4): 461-470.
[10] Yumeng Wang, Guiling Li. PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives[J]. Front. Med., 2019, 13(4): 438-450.
[11] Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao. Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects[J]. Front. Med., 2019, 13(4): 427-437.
[12] Tao Wang, Florent Chuffart, Ekaterina Bourova-Flin, Jin Wang, Jianqing Mi, Sophie Rousseaux, Saadi Khochbin. Histone variants: critical determinants in tumour heterogeneity[J]. Front. Med., 2019, 13(3): 289-297.
[13] Qiongna Dong, Bizhi Shi, Min Zhou, Huiping Gao, Xiaoying Luo, Zonghai Li, Hua Jiang. Growth suppression of colorectal cancer expressing S492R EGFR by monoclonal antibody CH12[J]. Front. Med., 2019, 13(1): 83-93.
[14] Synat Kang, Yanyan Li, Yifeng Bao, Yi Li. High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells[J]. Front. Med., 2019, 13(1): 69-82.
[15] Zhao Zhang, Jun Jiang, Xiaodong Wu, Mengyao Zhang, Dan Luo, Renyu Zhang, Shiyou Li, Youwen He, Huijie Bian, Zhinan Chen. Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy[J]. Front. Med., 2019, 13(1): 57-68.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed