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 | |
Wang, Hongbin1,2; Quan, Haitian1,2![]() ![]() | |
刊名 | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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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 |
DOI | 10.1016/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. |
资助项目 | National Natural Science Foundation of China[30801404] ; National Natural Science Foundation of China[81273546] ; National Science & Technology, China[2013ZX09102008] |
WOS关键词 | DOUBLE-BLIND ; MELANOMA ; THERAPY ; COMBINATION ; RESISTANCE ; TRAMETINIB ; NILOTINIB ; LEUKEMIA |
WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
语种 | 英语 |
出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
WOS记录号 | WOS:000403855600003 |
内容类型 | 期刊论文 |
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. |
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