Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
Vertex Pharmaceuticals (Europe) Ltd., Abingdon, Oxfordshire OX14 4RW, UK.
Cell Rep. 2016 Jan 12;14(2):298-309. doi: 10.1016/j.celrep.2015.12.032. Epub 2015 Dec 31.
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.
ATR 和 CHK1 在复制应激下维持癌细胞存活，目前这两种激酶的抑制剂都正在进行临床试验。由于 CHK1 抑制后 ATR 活性增加，我们假设这可能表明对 ATR 的生存依赖性增加。事实上，我们观察到，当与 ATR 抑制剂 VE-821 联合使用时，CHK1 抑制剂 AZD7762 诱导的复制应激会导致复制灾难和细胞凋亡，这种现象仅在癌细胞中发生。ATR 和 CHK1 抑制剂的联合治疗会导致复制叉停滞、ssDNA 积累、复制崩溃，并在体外和体内协同杀伤癌细胞。CDK 的抑制作用逆转了复制应激和合成致死性，表明 ATR 和 CHK1 对起始点的调控解释了合成致死性。总之，这项研究例证了同一路径中两种蛋白之间的肿瘤特异性合成致死性，并提出了联合应用 ATR 和 CHK1 抑制剂作为有前途的癌症治疗方法的前景。
