c-Myc Alterations Confer Therapeutic Response and Acquired Resistance to c-Met Inhibitors in MET-Addicted Cancers

doi:10.1158/0008-5472.CAN-14-2743

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	c-Myc Alterations Confer Therapeutic Response and Acquired Resistance to c-Met Inhibitors in MET-Addicted Cancers
	Shen, Aijun; Wang, Lu; Huang, Min; Sun, Jingya; Chen, Yi; Shen, Yan-Yan; Yang, Xinying; Wang, Xin; Ding, Jian; Geng, Meiyu
刊名	CANCER RESEARCH
	2015-11-01
卷号	75 期号:21 页码:4548-4559
ISSN号	0008-5472
DOI	10.1158/0008-5472.CAN-14-2743
文献子类	Article
英文摘要	Use of kinase inhibitors in cancer therapy leads invariably to acquired resistance stemming from kinase reprogramming. To overcome the dynamic nature of kinase adaptation, we asked whether a signal-integrating downstream effector might exist that provides a more applicable therapeutic target. In this study, we reported that the transcriptional factor c-Myc functions as a downstream effector to dictate the therapeutic response to c-Met inhibitors in c-Met-addicted cancer and derived resistance. Dissociation of c-Myc from c-Met control, likely overtaken by a variety of reprogrammed kinases, led to acquisition of drug resistance. Notably, c-Myc blockade by RNA interference or pharmacologic inhibition circumvented the acquired resistance to c-Met inhibition. Combining c-Myc blockade and c-Met inhibition in MET-amplified patient-derived xenograft mouse models heightened therapeutic activity. Our findings offer a preclinical proof of concept for the application of c-Myc-blocking agents as a tactic to thwart resistance to kinase inhibitors. (C) 2015 AACR.
资助项目	National Science and Technology Major Project of the Ministry of Science and Technology of China[2012ZX09301001-007] ; National Science and Technology Major Project of the Ministry of Science and Technology of China[2012ZX09301001-001] ; National Program on Key Basic Research Project of China[2012CB910704] ; Natural Science Foundation of China for Innovation Research Group[81321092] ; National Natural Science Foundation of China[91229205] ; National Natural Science Foundation of China[81222049] ; National Natural Science Foundation of China[81402966] ; Pujiang Scholar Program - Shanghai Metropolitan Government[12PJ1410400]
WOS关键词	RECEPTOR TYROSINE KINASE ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; CHRONIC MYELOID-LEUKEMIA ; CELL LUNG-CANCER ; DRUG-RESISTANCE ; ONCOGENE ADDICTION ; TUMOR XENOGRAFTS ; BIM ; EGFR ; AMPLIFICATION
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000365602200013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276339]
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	Geng, Meiyu
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Shen, Aijun,Wang, Lu,Huang, Min,et al. c-Myc Alterations Confer Therapeutic Response and Acquired Resistance to c-Met Inhibitors in MET-Addicted Cancers[J]. CANCER RESEARCH,2015,75(21):4548-4559.
APA	Shen, Aijun.,Wang, Lu.,Huang, Min.,Sun, Jingya.,Chen, Yi.,...&Geng, Meiyu.(2015).c-Myc Alterations Confer Therapeutic Response and Acquired Resistance to c-Met Inhibitors in MET-Addicted Cancers.CANCER RESEARCH,75(21),4548-4559.
MLA	Shen, Aijun,et al."c-Myc Alterations Confer Therapeutic Response and Acquired Resistance to c-Met Inhibitors in MET-Addicted Cancers".CANCER RESEARCH 75.21(2015):4548-4559.