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首页> 外文期刊>Cell Reports >Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities
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Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

机译：ATR和CHK1激酶活性之间的癌症特异性合成杀伤力

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ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy.
机译：ATR和CHK1在复制压力下维持癌细胞的存活，并且两种激酶的抑制剂目前都在进行临床试验。由于在CHK1抑制后ATR活性增加，因此我们推测这可能表明对ATR生存的依赖性增加。实际上，我们观察到，当与ATR抑制剂VE-821专门结合在癌细胞中时，由CHK1抑制剂AZD7762诱导的复制压力会导致复制灾难和凋亡。在体外和体内，ATR和CHK1抑制剂的联合治疗可导致复制叉停滞，ssDNA积累，复制塌陷和协同细胞死亡。抑制CDK可以逆转复制压力和合成杀伤力，这表明ATR和CHK1对原发射击的调节解释了合成杀伤力。总之，这项研究例证了同一途径中两种蛋白质之间特定于癌症的合成致死性，并提出了将ATR和CHK1抑制剂结合起来作为有前途的癌症治疗方法的前景。

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