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AKT is critically involved in the antagonism of BRAF inhibitor sorafenib against dabrafenib in colorectal cancer cells harboring both wild-type and mutant (V600E) BRAF genes

文献类型：期刊论文

作者Wang, Hongbin1,2; Quan, Haitian1,2; Lou, Liguang1,2
刊名BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
出版日期2017-07-15
卷号489期号:1页码:14-20
关键词Antagonism AKT BRAF Dabrafenib Sorafenib
ISSN号0006-291X
DOI10.1016/j.bbrc.2017.05.110
文献子类Article
英文摘要BRAF, one of the key factors in mitogen-activated protein kinase (MAPK) signaling pathway, plays an important role in cell functions including growth and proliferation. Inhibition of BRAF represents a promising antitumor strategy. Dabrafenib, a type I inhibitor of BRAF interrupting RAF/MEK interaction, has been approved by FDA as a single agent or combined with MEK inhibitor trametinib for the treatment of patients with BRAF V600E mutation-positive advanced melanoma. In the present study, we investigated the feasibility of combined treatment with dabrafenib and sorafenib, type I and type II BRAF inhibitor respectively, on colorectal cancer cells with BRAF V600E mutation. Unexpectedly, sorafenib significantly antagonized the inhibition effect of dabrafenib on the proliferation of colorectal cancer HT-29 and Co1o205 cells. The antagonism relied on co-existence of wild-type and mutant (V600E) BRAF, for no antagonism was observed in tumor cells expressing homozygous wild-type or mutant (V600E) BRAF. BRAF, but not CRAF, was required for this antagonism. Moreover, we found that sorafenib reversed dabrafenib inhibition of AKT in HT-29 cells, and phosphatidylinositol-3-kinase (PI3K) inhibitor GDC0941 significantly restored this antagonistic effect when combined with dabrafenib and sorafenib, indicating that AKT is critically involved in this antagonism. Collectively, we found that significant antagonism was observed when dabrafenib was combined with sorafenib in colorectal cancer cells harboring heterozygous genotype of BRAF and AKT is critically involved in this antagonism. We suggest that BRAF inhibitor dabrafenib and sorafenib should not be combined in clinic. (C) 2017 Elsevier Inc. All rights reserved.
WOS关键词DOUBLE-BLIND ; MELANOMA ; THERAPY ; COMBINATION ; RESISTANCE ; TRAMETINIB ; NILOTINIB ; LEUKEMIA
资助项目National Natural Science Foundation of China[30801404] ; National Natural Science Foundation of China[81273546] ; National Science & Technology, China[2013ZX09102008]
WOS研究方向Biochemistry & Molecular Biology ; Biophysics
语种英语
WOS记录号WOS:000403855600003
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/272566]  
专题药理学第一研究室
通讯作者Quan, Haitian; Lou, Liguang
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Wang, Hongbin,Quan, Haitian,Lou, Liguang. AKT is critically involved in the antagonism of BRAF inhibitor sorafenib against dabrafenib in colorectal cancer cells harboring both wild-type and mutant (V600E) BRAF genes[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2017,489(1):14-20.
APA Wang, Hongbin,Quan, Haitian,&Lou, Liguang.(2017).AKT is critically involved in the antagonism of BRAF inhibitor sorafenib against dabrafenib in colorectal cancer cells harboring both wild-type and mutant (V600E) BRAF genes.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,489(1),14-20.
MLA Wang, Hongbin,et al."AKT is critically involved in the antagonism of BRAF inhibitor sorafenib against dabrafenib in colorectal cancer cells harboring both wild-type and mutant (V600E) BRAF genes".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 489.1(2017):14-20.

入库方式： OAI收割

来源：上海药物研究所

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