Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer

Genome Medicine

Cor Lieftink¹  Roderick L. Beijersbergen¹  Bente Benedict²  Xiaohang Qiao²  Hein te Riele²  Frank van Gemert²  Chong Sun³  Shu Zhang⁴  Dongmei Gao⁴  Qiang Gao⁴  Hui Wang⁵  Yuchen Guo⁵  Chen Yang⁵  Xuhui Ma⁵  Jun Wang⁵  Cun Wang⁵  René Bernards⁵  Wenxin Qin⁵ 

[1] Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute;Division of Tumour Biology and Immunology, The Netherlands Cancer Institute;Immune Regulation in Cancer Group, German Cancer Research Center;Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education;State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine;

关键词: Hepatocellular carcinoma;    ATR-CHK1 signaling;    Replication stress;    Cell division cycle 7;   

DOI  :  10.1186/s13073-021-00981-0

来源: DOAJ

【 摘 要 】

Abstract Background Liver cancer is one of the most commonly diagnosed cancers and the fourth leading cause of cancer-related death worldwide. Broad-spectrum kinase inhibitors like sorafenib and lenvatinib provide only modest survival benefit to patients with hepatocellular carcinoma (HCC). This study aims to identify novel therapeutic strategies for HCC patients. Methods Integrated bioinformatics analyses and a non-biased CRISPR loss of function genetic screen were performed to identify potential therapeutic targets for HCC cells. Whole-transcriptome sequencing (RNA-Seq) and time-lapse live imaging were performed to explore the mechanisms of the synergy between CDC7 inhibition and ATR or CHK1 inhibitors in HCC cells. Multiple in vitro and in vivo assays were used to validate the synergistic effects. Results Through integrated bioinformatics analyses using the Cancer Dependency Map and the TCGA database, we identified ATR-CHK1 signaling as a therapeutic target for liver cancer. Pharmacological inhibition of ATR or CHK1 leads to robust proliferation inhibition in liver cancer cells having a high basal level of replication stress. For liver cancer cells that are resistant to ATR or CHK1 inhibition, treatment with CDC7 inhibitors induces strong DNA replication stress and consequently such drugs show striking synergy with ATR or CHK1 inhibitors. The synergy between ATR-CHK1 inhibition and CDC7 inhibition probably derives from abnormalities in mitosis inducing mitotic catastrophe. Conclusions Our data highlights the potential of targeting ATR-CHK1 signaling, either alone or in combination with CDC7 inhibition, for the treatment of liver cancer.

【 授权许可】

Unknown