CRISPR/Cas9 genome-wide screens for sensitisers and suppressors of AZD6738 efficacy in Atm WT and Atm KO mESCs

The protein kinase ATR plays pivotal roles in DNA repair, cell cycle checkpoint engagement and DNA replication. Consequently, ATR inhibitors (ATRi) are in clinical development for the treatment of cancers, including tumours harbouring mutations in the related kinase ATM. However, it still remains unclear which functions and pathways dominate long-term ATRi efficacy, and how these vary between clinically relevant genetic backgrounds. Elucidating common and genetic-background specific mechanisms of ATRi efficacy could therefore assist patient stratification and pre-empting drug resistance. Here, we use CRISPR-Cas9 genome-wide screening in ATM-deficient and proficient mouse embryonic stem cells to interrogate cell fitness following treatment with the ATRi, ceralasertib (AZD6738). We identify factors that enhance or suppress ATRi efficacy, with a subset of these requiring intact ATM signalling. Overall, our work identifies novel biomarkers of ATRi efficacy in ATM-proficient and ATM-deficien...