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Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer.
Guo, Yuchen; Wang, Jun; Benedict, Bente; Yang, Chen; van Gemert, Frank; Ma, Xuhui; Gao, Dongmei; Wang, Hui; Zhang, Shu; Lieftink, Cor; Beijersbergen, Roderick L; Te Riele, Hein; Qiao, Xiaohang; Gao, Qiang; Sun, Chong; Qin, Wenxin; Bernards, René; Wang, Cun.
Afiliação
  • Guo Y; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang J; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • Benedict B; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Yang C; Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • van Gemert F; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Ma X; Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • Gao D; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang H; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
  • Zhang S; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Lieftink C; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
  • Beijersbergen RL; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • Te Riele H; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • Qiao X; Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • Gao Q; Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • Sun C; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
  • Qin W; Immune Regulation in Cancer Group, German Cancer Research Center, D-69120, Heidelberg, Germany.
  • Bernards R; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang C; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. r.bernards@nki.nl.
Genome Med ; 13(1): 166, 2021 10 18.
Article em En | MEDLINE | ID: mdl-34663432
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteínas Serina-Treonina Quinases / Proteínas de Ciclo Celular / Replicação do DNA / Proteínas Mutadas de Ataxia Telangiectasia / Quinase 1 do Ponto de Checagem / Neoplasias Hepáticas Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteínas Serina-Treonina Quinases / Proteínas de Ciclo Celular / Replicação do DNA / Proteínas Mutadas de Ataxia Telangiectasia / Quinase 1 do Ponto de Checagem / Neoplasias Hepáticas Idioma: En Ano de publicação: 2021 Tipo de documento: Article