Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity
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…
A study reveals that a specific form of the PARP1 protein plays a key role in causing blood-related side effects when taking PARP inhibitors. These drugs, used to target certain cancers, can lead to severe anemia and an increased risk for leukemia in maintenance therapy. While the loss of PARP1 alone typically does not cause anemia in mice, the loss of PARP2 or its catalytic inactivation does.
This led researchers to focus on creating PARP1-selective inhibitors. However, their research found that these inhibitors also cause PARP1-dependent anemia in mice with either the wild-type, Parp1-/-, or Parp2-/- genetics. Furthermore, introducing a form of Parp1 that is catalytically inactive led to lethal bone marrow failure, something not seen with the deletion of both Parp1 and Parp2.
The scientists found that inactive PARP1 interferes with the repair of various DNA damages, unlike PARP2 which is more selective for nick damage. In cells, inactive PARP1 hinders PARP2's recruitment to DNA lesions, resulting in severe genomic instability and mitotic bridges, which are not observed in cells lacking both Parp1 and Parp2.
Therefore, the toxic effects seen with PARP inhibitors are primarily due to inactivation of PARP1, providing insight into the development of future, more effective PARP inhibitors.
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