DNA-PK enforces the S/G2 checkpoint in ATM-deficient cells to limit ATR inhibitor efficacy

DNA-PK activation after ATR inhibition enforces an S/G2 checkpoint in ATM-deficient cells and patient tumors, enabling tolerance of ATR inhibitor–induced replication stress.

• Why it matters: ATR inhibition is a proposed strategy for ATM-deficient tumors, but its anti-tumor activity is limited by DNA-PK and ATM compensation.
• What they did: The study delineated DNA-PK versus ATM roles during ATR inhibitor exposure, showing both kinases activate in a cell cycle–dependent manner at the S/G2 boundary, with DNA-PK enforcing S/G2 and ATM establishing a G2/M checkpoint.
• The result: In ATM-deficient cells and ATM-deficient PDX models, DNA-PK inhibition synergizes with ATR inhibition and enhances ATR inhibitor efficacy, supporting clinical evaluation of combined ATR and DNA-PK inhibition.