Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer

作     者：Junru Feng Hui Lu Wenhao Ma Wenjing Tian Zhuan Lu Hongying Yang Yongping Cai Pengfei Cai Yuchen Sun Zilong Zhou Jiaqian Feng Jiazhong Deng Ying Shu Kun Qu Weidong Jia Ping Gao Huafeng Zhang Junru Feng;Hui Lu;Wenhao Ma;Wenjing Tian;Zhuan Lu;Hongying Yang;Yongping Cai;Pengfei Cai;Yuchen Sun;Zilong Zhou;Jiaqian Feng;Jiazhong Deng;Ying Shu;Kun Qu;Weidong Jia;Ping Gao;Huafeng Zhang

作者机构：Anhui Key Laboratory of Hepatopancreatobiliary SurgeryDepartment of General SurgeryAnhui Provincial HospitalThe First Affiliated Hospital of USTCDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230027China Hefei National Laboratory for Physical Sciences at MicroscaleThe Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230027China Shenzhen People’s HospitalSecond Clinical Medical College of Jinan UniversityFirst Affiliated Hospital of Southern University of Science and TechnologyShenzhen 518000China Department of PathologySchool of MedicineAnhui Medical UniversityHefei 230032China School of Medicine and Institutes for Life SciencesSouth China University of TechnologyGuangzhou 510006China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2022年第13卷第11期

页      面：825-841页

核心收录：

学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 0703[理学-化学] 100214[医学-肿瘤学] 0836[工学-生物工程] 10[医学] 

基　　金：supported in part by National Key R&D Program of China(2018YFA0107103,2018YFA0800300) the Chinese Academy of Sciences(XDB39000000) National Natural Science Foundation of China(81930083,91957203,81821001,81525022) Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR110102001) the Program for Guangdong Introducing Innovative and Entrepreneurial Teams(2017ZT07S054) the Fundamental Research Funds for the Central Universities(YD2070002008,2020ZYGXZR038) 

主　　题：CRISPR screen DOCK1 hepatocellular carcinoma metformin small GTPase 

摘      要：Metformin is currently a strong candidate anti-tumor agent in multiple ***,its anti-tumor effectiveness varies among different cancers or sub-populations,potentially due to tumor *** thus remains unclear which hepatocellular carcinoma(HCC)patient subpopulation(s)can benefit from met-formin ***,through a genome-wide CRISPR-Cas9-based knockout screen,we find that DOCK1 levels determine the anti-tumor effects of met-formin and that DOCK1 is a synthetic lethal target of metformin in ***,metformin promotes DOCK1 phosphorylation,which activates RAC1 to facilitate cell survival,leading to metformin *** DOCK1-selective inhibitor,TBOPP,potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids,and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer ***,metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 *** study shows that metformin effective-ness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for met-formin-resistant HCC patients.