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Annual Review of Cancer Biology

Volume 9, 2025

Mechanism of Action of PARP Inhibitors

  • Chiho Kim1 and Yonghao Yu1
  • Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA; email: [email protected]
  • Vol. 9:225-244 (Volume publication date April 2025)
  • First published as a Review in Advance on December 03, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The selective vulnerability of mutated (mut) cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors provides one of the best examples of synthetic lethality that has been translated into the clinic. The success of this approach has led to a paradigm shift, with four PARP inhibitors now approved by the US Food and Drug Administration (FDA) for the treatment of ovarian, breast, prostate, and/or pancreatic cancers with mut. Furthermore, recent preclinical and clinical data suggest that many other types of solid tumors might also benefit from PARP inhibitors, regardless of their mut status. Despite this progress, resistance to PARP inhibitors is frequently observed in the clinic, which is, at least in part, due to the incomplete understanding of the mechanism of action of PARP inhibitors. In this review, we summarize the diverse processes underlying the signaling mechanisms of the PARP enzymes. We also discuss recent progress in utilizing these mechanistic insights for overcoming PARP inhibitor resistance, developing predictive biomarker assays, designing rational combination therapies, and, finally, developing the next-generation PARP1-targeting agents with a more complete and durable therapeutic response.

Keyword(s): next-generation PARP inhibitors, PARP inhibitors, PARP1 inhibition, PARP1 trapping, poly(ADP-ribose) polymerase inhibitors, resistance mechanisms, synthetic lethality
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2025-04-11
2025-06-19
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Mechanism of Action of PARP Inhibitors
Annual Review of Cancer Biology 9, 225 (2025); https://doi.org/10.1146/annurev-cancerbio-042324-103725
/content/journals/10.1146/annurev-cancerbio-042324-103725
/content/journals/10.1146/annurev-cancerbio-042324-103725
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