机构：[1]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.[2]Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.[3]State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[4]Bioinformatics and Systems Medicine Laboratory, Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA.[5]Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.[6]Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21(WAF1/CIP1), leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21(WAF1/CIP1), either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21(WAF1/CIP1). Co-administration of BI-2536 and fasudil either in the LSL-KRAS(G12D) mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers.
基金：
This work is supported by the Fundamental Research Funds for the Central
Universities (78260029), National Natural Science Foundation of China (81101683 and
81330049), grants from National Basic Research Program of China (2012CB910401) and
the Science and Technology Commission of Shanghai Municipality (16ZR1410400 and
14DZ2270100), and a fellowship from the State Scholarship Council (201506145040).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2016]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.[2]Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
共同第一作者：
通讯作者：
通讯机构：[1]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.[6]Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
推荐引用方式(GB/T 7714)：
Wang Jieqiong,Hu Kewen,Guo Jiawei,et al.Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK.[J].Nature communications.2016,7:11363.doi:10.1038/ncomms11363.
APA：
Wang Jieqiong,Hu Kewen,Guo Jiawei,Cheng Feixiong,Lv Jing...&Liu Mingyao.(2016).Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK..Nature communications,7,
MLA：
Wang Jieqiong,et al."Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK.".Nature communications 7.(2016):11363
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