Metformin is currently a strong candidate anti-tumor agent in multiple cancers.However,its anti-tumor effectiveness varies among different cancers or sub-populations,potentially due to tumor heterogeneity.It thus remains unclear which hepatocellular carcinoma(HCC)patient subpopulation(s)can benefit from met-formin treatment.Here,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 HCC.Mechanistically,metformin promotes DOCK1 phosphorylation,which activates RAC1 to facilitate cell survival,leading to metformin resistance.The 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 models.Notably,metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression.This 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.

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

Anhui Key Laboratory of Hepatopancreatobiliary Surgery,Department of General Surgery,Anhui Provincial Hospital,The First Affiliated Hospital of USTC,Division of Life Science and Medicine,University of Science and Technology of China,Hefei 230027,China;Hefei National Laboratory for Physical Sciences at Microscale,The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease,School of Basic Medical Sciences,Division of Life Science and Medicine,University of Science and Technology of China,Hefei 230027,China;Shenzhen People's Hospital,Second Clinical Medical College of Jinan University,First Affiliated Hospital of Southern University of Science and Technology,Shenzhen 518000,China;Department of Pathology,School of Medicine,Anhui Medical University,Hefei 230032,China;School of Medicine and Institutes for Life Sciences,South China University of Technology,Guangzhou 510006,China

蛋白质与细胞

[1]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-.Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer)[J].蛋白质与细胞,2022(11):825-841

formin,TBOPP

Genome,wide,CRISPR,screen,identifies,synthetic,lethality,between,DOCK1,inhibition,metformin,liver,Metformin,currently,strong,candidate,anti,tumor,agent,multiple,cancers,However,its,effectiveness,varies,among,different,populations,potentially,due,heterogeneity,It,thus,remains,unclear,which,hepatocellular,carcinoma,HCC,subpopulation,benefit,from,treatment,Here,through,genome,Cas9,knockout,find,that,levels,determine,effects,target,Mechanistically,promotes,phosphorylation,activates,RAC1,facilitate,survival,leading,resistance,selective,inhibitor,potentiates,activity,by,vitro,lines,derived,organoids,vivo,xenografted,cells,immunocompetent,mouse,models,Notably,improves,overall,patients,low,but,not,high,expression,This,study,shows,depends,combining,may,provide,promising,personalized,therapeutic,strategy,resistant

0.52634