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Preprint WatchMildOctober 28th, 2026

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

Branigan, T. B.; Alharthi, R.; Kochupurakkal, B. S.; Hao, J.; Revia, S.; Albers, J.; Cai, M.-Y.; Jiao, Y.; McQueen, K.; Mukkavalli, S.; Roundtree, I. A.; Cote, G. M.; Gokhale, P. C.; Parmar, K.; D'Andrea, A. D.; Zimmermann, A.; Shapiro, G. I.

DNA-PK enforces the S/G2 checkpoint in ATM-deficient cells and compensates for ATR inhibition, so DNA-PK inhibition synergises with ATR inhibition and restores efficacy in ATM-deficient PDX models.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The preprint reports that DNA-PK enforces the S/G2 checkpoint in ATM-deficient cells and substitutes for ATM in detecting aberrant replication structures, so cells tolerate ATR inhibition unless DNA-PK is also blocked, with combined inhibition enhancing activity in ATM-deficient patient-derived xenograft models. Claidex holds one ATR failure, ceralasertib-atr-advanced-solid-tumours-phase1-programme-discontinuation, a Phase 1 programme in unselected advanced solid tumours that ended for strategic rather than efficacy reasons. The preprint does not contradict that record, and it offers a mechanistic reason why single-agent ATR inhibition in an unselected population would be expected to underperform, since the compensating kinase is present in most tumours and ATM loss alone does not remove it. Flagged MILD because the one matching failure was not an efficacy failure.

Abstract excerpt

ATR inhibition has been proposed as a strategy for tumors under replication stress or those harboring ATM deficiency. However, anti-tumor activity is limited by DNA-PK and ATM compensation. Here, we have delineated distinct roles for DNA-PK and ATM during ATR inhibitor exposure. Both kinases are activated in a cell cycle-dependent manner at the S/G2 boundary following ATR inhibition. DNA-PK imposes the S/G2 checkpoint and promotes completion of DNA replication, whereas ATM detects persistent aberrant DNA replication structures with associated DNA damage in late S and G2/M to establish a G2/M checkpoint promoting DNA repair. In ATM-deficient cells and patient tumors, DNA-PK is activated following ATR inhibition and assumes greater versatility by not only enforcing the S/G2 checkpoint but also by detecting aberrant replication structures in S phase in place of ATM, allowing cells to tolerate ATR inhibition. Consequently, DNA-PK inhibition synergizes with ATR inhibition in ATM-deficient cells and enhances ATR inhibitor efficacy in ATM-deficient PDX models. These data support clinical evaluation of combined ATR and DNA-PK inhibition in ATM-deficient cancers.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.