Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

•Synthetic lethality within the same pathway is via the induction of replication catastrophe•New origin firing and replication stress induced by CHK1 inhibitor reliance on ATR•ATR and CHK1 inhibitor combination results in cancer-specific cytotoxicity•ATR and CHK1 inhibitor combination could be used broadly across cancer indications

SummaryATR 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide