Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer.
Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer.
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全基因组 CRISPR 筛选鉴定了 DOCK1 抑制和二甲双胍在肝癌中的合成致死率。
DOI：
10.1007/s13238-022-00906-6
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发表时间：
2022-11
期刊：
影响因子：
21.1
通讯作者：
Zhang, Huafeng
中科院分区：
文献类型：
--
作者：
Feng, Junru;Lu, Hui;Ma, Wenhao;Tian, Wenjing;Lu, Zhuan;Yang, Hongying;Cai, Yongping;Cai, Pengfei;Sun, Yuchen;Zhou, Zilong;Feng, Jiaqian;Deng, Jiazhong;Shu, Ying;Qu, Kun;Jia, Weidong;Gao, Ping;Zhang, Huafeng
Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin 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 effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients. The online version contains supplementary material available at 10.1007/s13238-022-00906-6.
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影响因子：
29
作者：
Lord SR;Cheng WC;Liu D;Gaude E;Haider S;Metcalf T;Patel N;Teoh EJ;Gleeson F;Bradley K;Wigfield S;Zois C;McGowan DR;Ah-See ML;Thompson AM;Sharma A;Bidaut L;Pollak M;Roy PG;Karpe F;James T;English R;Adams RF;Campo L;Ayers L;Snell C;Roxanis I;Frezza C;Fenwick JD;Buffa FM;Harris AL
通讯作者：
Harris AL
影响因子：
10.5
作者：
Guo X;Zhao Y;Yan H;Yang Y;Shen S;Dai X;Ji X;Ji F;Gong XG;Li L;Bai X;Feng XH;Liang T;Ji J;Chen L;Wang H;Zhao B
通讯作者：
Zhao B
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
10.5
作者：
Laurin M;Côté JF
通讯作者：
Côté JF
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi