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  3. 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

  • Protein Cell. 2022 Nov;13(11):825-841. doi: 10.1007/s13238-022-00906-6.
Junru Feng  # 1 2,  Hui Lu  # 1 2,  Wenhao Ma 2,  Wenjing Tian 1 2,  Zhuan Lu 1,  Hongying Yang 3,  Yongping Cai 4,  Pengfei Cai 2,  Yuchen Sun 2,  Zilong Zhou 2,  Jiaqian Feng 2,  Jiazhong Deng 1,  Ying Shu 2,  Kun Qu 2,  Weidong Jia 5,  Ping Gao 6 7,  Huafeng Zhang 8 9
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518000, China.
  • 4 Department of Pathology, School of Medicine, Anhui Medical University, Hefei, 230032, China.
  • 5 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. [email protected].
  • 6 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. [email protected].
  • 7 School of Medicine and Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China. [email protected].
  • 8 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. [email protected].
  • 9 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. [email protected].
  • # Contributed equally.
PMID: 35217990 DOI: 10.1007/s13238-022-00906-6
Abstract

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.

Keywords

CRISPR screen; DOCK1; hepatocellular carcinoma; metformin; small GTPase.

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