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

• DOI: 10.1007/s13238-022-00906-6
• Publication Date: 2022-02-26T04:31:42Z
• Authors: 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
• Keywords: Liver Cancer

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its 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 genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the effects of and synthetic lethal target HCC. Mechanistically, promotes phosphorylation, activates RAC1 facilitate cell survival, leading resistance. The DOCK1-selective inhibitor, TBOPP, potentiates activity by vitro liver cancer lines patient-derived HCC organoids, vivo xenografted cells immunocompetent mouse models. Notably, improves overall survival patients with low but not high expression. This study shows depends on combining inhibition may provide promising personalized therapeutic strategy for metformin-resistant patients.