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Understanding and overcoming resistance to PARP inhibitors in cancer therapy

Abstract

Developing novel targeted anticancer therapies is a major goal of current research. The use of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with homologous recombination-deficient tumours provides one of the best examples of a targeted therapy that has been successfully translated into the clinic. The success of this approach has so far led to the approval of four different PARP inhibitors for the treatment of several types of cancers and a total of seven different compounds are currently under clinical investigation for various indications. Clinical trials have demonstrated promising response rates among patients receiving PARP inhibitors, although the majority will inevitably develop resistance. Preclinical and clinical data have revealed multiple mechanisms of resistance and current efforts are focused on developing strategies to address this challenge. In this Review, we summarize the diverse processes underlying resistance to PARP inhibitors and discuss the potential strategies that might overcome these mechanisms such as combinations with chemotherapies, targeting the acquired vulnerabilities associated with resistance to PARP inhibitors or suppressing genomic instability.

Key points

  • BRCA1/2-deficient cells are extremely vulnerable to PARP inhibition; this finding has led to the successful clinical development of PARP inhibitors for the treatment of patients with BRCA1/2-mutant cancers.

  • The use of PARP inhibitors is currently being expanded beyond patients with ovarian and breast cancers to those with homologous recombination-deficient tumours of other histologies such as prostate or pancreatic cancers.

  • Resistance to PARP inhibitors occurs through three main mechanisms: drug target-related resistance, restoration of homologous recombination and restoration of replication fork stability.

  • Current approaches to overcome resistance are focused on combining PARP inhibition with other inhibitors of the DNA damage response, immune-checkpoint inhibition or targeted therapies.

  • Targeting the acquired vulnerabilities of PARP inhibitor-resistant tumours might selectively kill unresponsive cancer cells.

  • Preventing the development of genomic instability in DNA repair-deficient cancers by inhibiting the activity of the error-prone polymerase POLθ might be a promising strategy to target a known vulnerability of these tumours.

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Fig. 1: PARP inhibitors and their mechanism of action.
Fig. 2: Mechanisms of resistance to PARP inhibitors.
Fig. 3: Mechanisms of BRCA1-independent restoration of HR.
Fig. 4: Overcoming resistance to PARP inhibitors.
Fig. 5: Targeting acquired vulnerabilities of PARP inhibitor-resistant tumours.

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Acknowledgements

Work in J.J.’s laboratory was funded by the Oncode Institute, which is partly financed by the Dutch Cancer Society. The work of M.P.D. is supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 722729. The work of S.C.M. is supported by Boehringer Ingelheim Fonds. S.G. has received funding from the NCI (grants R01-CA243547, RO1-CA202752 and 5P30CA072720-21), US Department of Defence, the Breast Cancer Research Foundation, Hugs for Brady, the Val Skinner Foundation, the Gertrude Fogarty Trust and AHEPA.

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M.P.D. and S.C.M. made substantial contributions to researching data for this article and discussions of content. All authors contributed to writing the article and reviewing/editing of the manuscript before submission.

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Correspondence to Shridar Ganesan or Jos Jonkers.

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J.J. has acted as a consultant of and received research support from Artios Pharma. S.G. has acted as a consultant of Foghorn Therapeutics, Foundation Medicine, Inspirata, Merck, Novartis, and Roche and has received research funding from M2Gen; his spouse is an employee of Merck and holds equity in Merck. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks G. Peng and I. Ray-Coquard for their contribution to the peer review of this work.

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Dias, M.P., Moser, S.C., Ganesan, S. et al. Understanding and overcoming resistance to PARP inhibitors in cancer therapy. Nat Rev Clin Oncol 18, 773–791 (2021). https://doi.org/10.1038/s41571-021-00532-x

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