Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer.
Targeting CDC7 potentiates ATR-CHK1 signaling inhibition through induction of DNA replication stress in liver cancer.
复制标题
靶向 CDC7 通过诱导肝癌中的 DNA 复制应激来增强 ATR-CHK1 信号传导抑制
DOI：
10.1186/s13073-021-00981-0
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发表时间：
2021-10-18
期刊：
影响因子：
12.3
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Guo Y;Wang J;Benedict B;Yang C;van Gemert F;Ma X;Gao D;Wang H;Zhang S;Lieftink C;Beijersbergen RL;Te Riele H;Qiao X;Gao Q;Sun C;Qin W;Bernards R;Wang C
背景肝癌是最常见的癌症之一，也是全球第四大癌症相关死亡原因。广谱激酶抑制剂如索拉非尼和乐伐替尼仅为肝细胞癌（HCC）患者提供适度的生存获益。本研究旨在为HCC patient.MethodsIntegrated生物信息学分析和非偏倚CRISPR功能缺失基因筛选确定HCC细胞的潜在治疗靶点。通过全转录组测序（RNA-Seq）和延时实时成像来探讨CDC 7抑制剂与ATR或CHK 1抑制剂在HCC细胞中的协同作用机制。多个在体外和体内检测被用来验证的协同effects.ResultsThrough集成的生物信息学分析，使用癌症Dependency Map和TCGA数据库，我们确定了ATR-CHK 1信号作为肝癌的治疗靶点。ATR或CHK 1的药理学抑制导致具有高基础水平复制应激的肝癌细胞中的稳健增殖抑制。对于对ATR或CHK 1抑制有抗性的肝癌细胞，用CDC 7抑制剂治疗诱导强DNA复制应激，因此这些药物显示出与ATR或CHK 1抑制剂的显著协同作用。ATR-CHK 1抑制和CDC 7抑制之间的协同作用可能来自有丝分裂异常诱导有丝分裂catastrophe.ConclusionsOur数据突出了针对ATR-CHK 1信号传导的潜力，无论是单独或与CDC 7抑制相结合，用于治疗肝癌。
BackgroundLiver 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.MethodsIntegrated 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.ResultsThrough 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.ConclusionsOur 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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影响因子：
16
作者：
Buisson R;Boisvert JL;Benes CH;Zou L
通讯作者：
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影响因子：
11.2
作者：
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影响因子：
64.5
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通讯作者：
Cancer Genome Atlas Research Network
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作者：
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影响因子：
22.7
作者：
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通讯作者：
Golub, Todd R.