c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors

doi:10.1158/1078-0432.CCR-15-2448

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	c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors
	Liu, Hongyan; Ai, Jing; Shen, Aijun; Chen, Yi; Wang, Xinyi; Peng, Xia; Chen, Hui; Shen, Yanyan; Huang, Min; Ding, Jian
刊名	CLINICAL CANCER RESEARCH
	2017-02
卷号	23 期号:4 页码:974-984
ISSN号	1078-0432
DOI	10.1158/1078-0432.CCR-15-2448
文献子类	Article
英文摘要	Purpose: Lately, emerging evidence has suggested that oncogenic kinases are associated with specific downstream effectors to govern tumor growth, suggesting potential translational values in kinase-targeted cancer therapy. Tyrosine kinase FGFR, which is aberrant in various cancer types, is one of the most investigated kinases in molecularly targeted cancer therapy. Herein, we investigated whether there exists key downstream effector(s) that converges FGFR signaling and determines the therapeutic response of FGFR-targeted therapy. Experimental Design: A range of assays was used to assess the role of c-Myc in FGFR aberrant cancers and its translational relevance in FGFR-targeted therapy, including assessment of drug sensitivity using cell viability assay, signaling transduction profiling using immunoblotting, and in vivo antitumor efficacy using cancer cell line-based xenografts and patient-derived xenografts models. Results: We discovered that c-Myc functioned as the key downstream effector that preceded FGFR-MEK/ERK signaling in FGFR aberrant cancer. Disruption of c-Myc overrode the cell proliferation driven by constitutively active FGFR. FGFR inhibition in FGFR-addicted cancer facilitated c-Myc degradation via phosphorylating c-Myc at threonine 58. Ectopic expression of undegradable c-Myc mutant conferred resistance to FGFR inhibition both in vitro and in vivo. c-Myc level alteration stringently determined the response to FGFR inhibitors, as demonstrated in FGFR-responsive cancer subset, as well as cancers bearing acquired or de novo resistance to FGFR inhibition. Conclusions: This study reveals a stringent association between FGFR and the downstream effector c-Myc in FGFR-dependent cancers, and suggests the potential therapeutic value of c-Myc in FGFR-targeted cancer therapy. (C)2016 AACR.
资助项目	National Program on Key Basic Research Project of China[2012CB910704] ; National Key Sci-Tech Project[2012ZX09301001-007] ; Natural Science Foundation of China[81321092] ; Natural Science Foundation of China[81473243] ; Natural Science Foundation of China[81222049] ; Natural Science Foundation of China[81402966] ; Chinese Academy of Sciences[XDA12020101] ; Youth Innovation Promotion Association[00000000]
WOS关键词	CELL-CYCLE ARREST ; BREAST-CANCER ; LUNG-CANCER ; MAMMALIAN TARGET ; EXPRESSION ; VEMURAFENIB ; SENSITIVITY ; RESISTANCE ; ADDICTION ; PHENOTYPE
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000393885700012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275650]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Huang, Min; Ding, Jian; Geng, Meiyu
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Liu, Hongyan,Ai, Jing,Shen, Aijun,et al. c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors[J]. CLINICAL CANCER RESEARCH,2017,23(4):974-984.
APA	Liu, Hongyan.,Ai, Jing.,Shen, Aijun.,Chen, Yi.,Wang, Xinyi.,...&Geng, Meiyu.(2017).c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors.CLINICAL CANCER RESEARCH,23(4),974-984.
MLA	Liu, Hongyan,et al."c-Myc Alteration Determines the Therapeutic Response to FGFR Inhibitors".CLINICAL CANCER RESEARCH 23.4(2017):974-984.