EPHA2 feedback activation limits the response to PDE delta inhibition in KRAS-dependent cancer cells

doi:10.1038/s41401-019-0268-y

	EPHA2 feedback activation limits the response to PDE delta inhibition in KRAS-dependent cancer cells
	Chen, Yue-hong 1,3; Lv, Hao 3,4; Shen, Ning 3; Wang, Xiao-min 3,4; Tang, Shuai 3; Xiong, Bing 2; Ding, Jian 3,4; Geng, Mei-yu 3,4; Huang, Min 3,4
刊名	ACTA PHARMACOLOGICA SINICA
	2020-02-01
卷号	41 期号:2 页码:270-277
关键词	KRAS anticancer therapy PDE delta EPHA2 RAF MEK ERK signaling
ISSN号	1671-4083
DOI	10.1038/s41401-019-0268-y
通讯作者	Huang, Min(mhuang@simm.ac.cn)
英文摘要	KRAS is one of the most important proto-oncogenes. Its mutations occur in almost all tumor types, and KRAS mutant cancer is still lack of effective therapy. Prenyl-binding protein phosphodiesterase-delta (PDE delta) is required for the plasma membrane association and subsequent activation of KRAS oncogenic signaling. Recently, targeting PDE delta has provided new promise for KRAS mutant tumors. However, the therapeutic potential of PDE delta inhibition remains obscure. In this study, we explored how PDE delta inhibition was responded in KRAS mutant cancer cells, and identified KRAS mutant subset responsive to PDE delta inhibition. We first performed siRNA screen of KRAS growth dependency of a small panel of human cancer lines, and identified a subset of KRAS mutant cancer cells that were highly dependent on KRAS signaling. Among these cells, only a fraction of KRAS-dependent cells responded to PDE delta depletion, though KRAS plasma membrane association was effectively impaired. We revealed that the persistent RAF/MEK/ERK signaling seemed responsible for the lack of response to PDE delta depletion. A kinase array further identified that the feedback activation of EPH receptor A2 (EPHA2) accounted for the compensatory activation of RAF/MEK/ERK signaling in these cells. Simultaneous inhibition of EPHA2 and PDE delta led to the growth inhibition of KRAS mutant cancer cells. Together, this study gains a better understanding of PDE delta-targeted therapeutic strategy and suggests the combined inhibition of EPHA2 and PDE delta as a potential therapy for KRAS mutant cancer.
资助项目	National Natural Science Foundation of China[81821005] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020345] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020230]
WOS关键词	SIGNALING PATHWAY ; RAS ONCOGENES ; RECEPTOR
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000510769500014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281691]
专题	中国科学院上海药物研究所
通讯作者	Huang, Min
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 3.Shanghai Univ, Sch Life Sci, Shanghai 200444, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Chen, Yue-hong,Lv, Hao,Shen, Ning,et al. EPHA2 feedback activation limits the response to PDE delta inhibition in KRAS-dependent cancer cells[J]. ACTA PHARMACOLOGICA SINICA,2020,41(2):270-277.
APA	Chen, Yue-hong.,Lv, Hao.,Shen, Ning.,Wang, Xiao-min.,Tang, Shuai.,...&Huang, Min.(2020).EPHA2 feedback activation limits the response to PDE delta inhibition in KRAS-dependent cancer cells.ACTA PHARMACOLOGICA SINICA,41(2),270-277.
MLA	Chen, Yue-hong,et al."EPHA2 feedback activation limits the response to PDE delta inhibition in KRAS-dependent cancer cells".ACTA PHARMACOLOGICA SINICA 41.2(2020):270-277.