DNA-PK sustains the S/G2 checkpoint in ATM-deficient cells, blunting ATR inhibitors
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A preprint study posted to bioRxiv on 28 October 2026 shows that DNA-PK maintains the S/G2 checkpoint in cells lacking ATM function, compensating for the loss of ATM and limiting how well ATR inhibitors work. After ATR inhibition, both DNA-PK and ATM are activated at the S/G2 boundary; without ATM, DNA-PK additionally senses aberrant replication structures during S phase, allowing cells to tolerate ATR inhibition. Blocking ATR and DNA-PK together proved synergistic in ATM-deficient cells and improved efficacy in ATM-deficient patient-derived xenograft models. The findings support clinical evaluation of combined ATR and DNA-PK inhibition in ATM-deficient cancers. What remains open is translating the combination into patients: trial design, dosing and patient selection for ATM-deficient tumors have yet to be worked out.
Written by a model from the reports · updated 3 hours ago
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- biorxiv.orgPickDNA-PK enforces the S/G2 checkpoint in ATM-deficient cells to limit ATR inhibitor efficacy
A study shows that DNA-PK maintains the S/G2 checkpoint in ATM-deficient cells and compensates for loss of ATM function, limiting ATR inhibitor efficacy. After ATR inhibition, DNA-PK and ATM are activated at the S/G2 boundary; when ATM is absent, DNA-PK also detects aberrant replication structures in S phase, allowing cells to tolerate ATR inhibition. Combined ATR and DNA-PK inhibition is synergistic in ATM-deficient cells and enhances efficacy in ATM-deficient PDX models, supporting clinical evaluation in ATM-deficient cancers.
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