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Preprint WatchModerateSeptember 25th, 2026

Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity

Lin X, Shao Z, Yaneva D, Jiang W, Menolfi D, Bhandari SK, Lee BJ, Schmucker M, Yaneva F, Tomkinson AE, Stingele J, Zha S.

Haematological toxicity of approved PARP inhibitors is driven primarily by trapping of catalytically inactive PARP1 protein on chromatin rather than by loss of PARylation, which predicts that PARP1-selective inhibitors will not escape the toxicity that motivated their development.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Lin and colleagues report that the anaemia and leukaemia risk seen with approved PARP inhibitors is driven by trapping of catalytically inactive PARP1 protein rather than by loss of PARylation, using wild-type, Parp1 null and Parp2 null mice. If that holds, the rationale for PARP1-selective inhibitors as a lower toxicity class is weakened at the mechanism level. Two PARP1 entries are already on file. talazoparib-temozolomide-parp1-ddr-wild-type-mcrpc-phase1b2-translational-mismatch records a combination stopped for translational mismatch in DNA damage response wild-type prostate cancer, and olaparib-pembrolizumab-parp1-metastatic-tnbc-keylynk-009-phase2-maintenance-efficacy-failure records an efficacy failure in triple-negative breast cancer. Both failures were about where the benefit was sought rather than about tolerability. This preprint sharpens the other half of the ledger, since a class whose therapeutic window is set by trapping cannot widen that window by removing catalysis alone.

Abstract excerpt

Dual PARP1/2 inhibitors (PARPi) selectively eliminate BRCA1/2-deficient cancers and represent the first targeted therapy for homologous recombination (HR)-deficient cancers. However, their use in maintenance therapy is limited by severe anemia and an increased risk for therapy-related leukemia. These toxicities are unexpected because PARP1 loss, which eliminates most DNA-damage-induced PARylation, does not cause anemia in mice. In contrast, PARP2 loss or catalytic inactivation causes anemia, motivating the development of PARP1-selective inhibitors. Using wild-type (WT), Parp1-/- and Parp2-/- mice, we show that hematopoietic toxicity of FDA-approved PARPi is driven primarily by inactive PARP1 rather than PARP2 inhibition. Accordingly, PARP1-selective inhibitors also cause PARP1-dependent anemia. Somatic expression of catalytically inactive Parp1 (Parp1E988A) causes lethal bone marrow failure, not found with somatic deletion of both Parp1&2. Mechanistically, inactive PARP1 obstructs the repair of diverse DNA lesions, including gaps, nicks, and Top1-cc, in contrast to the nick-selectivity of Parp2. In cells, inactive PARP1 compromises PARP2 recruitment to DNA lesions and causes severe genomic instability and mitotic bridges absent in Parp1&2-null cells. Thus, PARPi-induced hematopoietic toxicity is driven primarily by PARP1 inactivation, informing the design and use of next-generation PARP inhibitors.

Matching Claidex post-mortems

2 of 2 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.