Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells

doi:10.18632/oncotarget.14009

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

	Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells
	Song, Qiaoling 1,2; Sun, Xiaoxiao 1,2; Guo, Hui 1,2; Yu, Qiang1,2
刊名	ONCOTARGET
	2017-01-17
卷号	8 期号:3 页码:5003-5015
关键词	receptor tyrosine kinases AKT colorectal cancer drug combination RAS/RAF
ISSN号	1949-2553
DOI	10.18632/oncotarget.14009
文献子类	Article
英文摘要	Receptor tyrosine kinase (RTK) signaling pathways are frequently activated in cancer cells due to mutations of RTKs and/or their downstream signaling proteins such as KRAS and BRAF. About 40% colorectal cancers (CRCs) contain KRAS or BRAF mutant genes and are resistant to treatments with individual inhibitors of RTKs, AKT, MEK, or BRAF. Therefore, an understanding of the molecular mechanisms of the drug resistance is necessary for developing effective strategies to treat the diseases. Here we report the discovery of an AKT/ERK reactivation mechanism that account for the cancer cell resistance to the AKT and MEK inhibitors treatments. The reactivations of AKT and ERK after the AKT or MEK inhibitor treatment were caused by a relief of an AKT or ERK-mediated feedback inhibition of the RTKs and/or their downstream pathways. A combination of RTK inhibitors, based on the RTK activation/phosphorylation profile, synergized with the AKT inhibitor, but not the MEK inhibitor, to completely inhibit the AKT phosphorylation and to block the growth of KRAS/BRAF mutant CRC cells. These results underscored the importance of AKT and the AKT feedback signaling to cancer cell growth and offered a novel therapeutic approach for the treatment of KRAS/BRAF mutant CRC cells.
资助项目	China Ministry of Science and Technology Key New Drug Creation and Manufacturing Program[2014ZX09102001-002] ; China Ministry of Science and Technology Key New Drug Creation and Manufacturing Program[2013ZX09102015] ; China Ministry of Science and Technology Key New Drug Creation and Manufacturing Program[2013ZX10002010-009] ; National Natural Science Foundation of China[81302792] ; National Natural Science Foundation of China[81373447] ; National Natural Science Foundation of China[91413121] ; National Natural Science Foundation of China[91213304] ; China National Key Basic Research Program[2012CB910704] ; China National Key Basic Research Program[2013CB910904]
WOS关键词	TARGETED INHIBITORS ; INSULIN-RECEPTOR ; BRAF INHIBITION ; MEK INHIBITION ; IN-VITRO ; MELANOMA ; THERAPY ; RAS ; ACTIVATION ; COMPLEXITY
WOS研究方向	Oncology ; Cell Biology
语种	英语
出版者	IMPACT JOURNALS LLC
WOS记录号	WOS:000393228400100
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275673]
专题	药理学第一研究室
通讯作者	Yu, Qiang
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Medica, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Song, Qiaoling,Sun, Xiaoxiao,Guo, Hui,et al. Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells[J]. ONCOTARGET,2017,8(3):5003-5015.
APA	Song, Qiaoling,Sun, Xiaoxiao,Guo, Hui,&Yu, Qiang.(2017).Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells.ONCOTARGET,8(3),5003-5015.
MLA	Song, Qiaoling,et al."Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells".ONCOTARGET 8.3(2017):5003-5015.