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Review
. 2023 Oct;129(6):904-916.
doi: 10.1038/s41416-023-02326-7. Epub 2023 Jul 10.

PARP inhibitors: enhancing efficacy through rational combinations

Affiliations
Review

PARP inhibitors: enhancing efficacy through rational combinations

Deepak Bhamidipati et al. Br J Cancer. 2023 Oct.

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) have significantly changed the treatment landscape for tumours harbouring defects in genes involved in homologous repair (HR) such as BRCA1 and BRCA2. Despite initial responsiveness to PARPi, tumours eventually develop resistance through a variety of mechanisms. Rational combination strategies involving PARPi have been explored and are in various stages of clinical development. PARPi combinations have the potential to enhance efficacy through synergistic activity, and also potentially sensitise innately PARPi-resistant tumours to PARPi. Initial combinations involving PARPi with chemotherapy were hindered by significant overlapping haematologic toxicity, but newer combinations with fewer toxicities and more targeted approaches are undergoing evaluation. In this review, we discuss the mechanisms of PARPi resistance and review the rationale and clinical evidence for various PARPi combinations including combinations with chemotherapy, immunotherapy, and targeted therapies. We also highlight emerging PARPi combinations with promising preclinical evidence.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Emerging targets for rational combinations with PARP inhibitors.
The figure displays various pathways that modulate response to DNA damage and are identified as key targets in combination with PARP inhibitors. The receptor tyrosine kinase cascade mediated by the EGFR, VEGF and c-MET receptors with downstream effectors such as the RAS/MEK and PI3K/AKT pathways are hypothesised to increase homologous repair capacity. Pathways and proteins involved in cell cycle progression such as ATR and WEE1 play an integral role in response to DNA damage in addition to emerging targets USP1 and POLQ. DNA damage mediated by PARP inhibitors is hypothesised to increase T-cell recruitment via activation of the cGAS-STING pathway.

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