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 rema...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.展开更多
基金supported in part by National Key R&D Program of China(2018YFA0107103,2018YFA0800300)the Chinese Academy of Sciences(XDB39000000)+3 种基金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).
文摘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.
