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PARP Inhibitors

Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer

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Abstract

The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of-concept for a synthetic lethal anticancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.

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Acknowledgements

Bristi Basu and Shahneen K. Sandhu contributed equally to this article.

The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported by a programme grant from Cancer Research UK, the Experimental Cancer Medicine Centre grant (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre grant (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). JSB has served as a paid consultant for Pfizer, Genentech, Novartis, Astellas, Boehringer Inhleheim, Merck, and AstraZeneca. No disclosures were declared for the rest of the authors.

Bristi Basu is currently employed by the Cambridge University Hospitals NHS Foundation Trust.

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  1. Drug Development Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK

    Bristi Basu, Shahneen K. Sandhu &  Johann S. de Bono MBChB, MSc, PhD, FRCP (Professor in Experimental Cancer Medicine, Section of Medicine)

  2. The Institute of Cancer Research, Drug Development Unit, Royal Marsden NHS Foundation Trust, Downs Road Sutton, Surrey, SM2 5PT, UK

    Bristi Basu, Shahneen K. Sandhu &  Johann S. de Bono MBChB, MSc, PhD, FRCP (Professor in Experimental Cancer Medicine, Section of Medicine)

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  1. Bristi Basu
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Correspondence to Johann S. de Bono MBChB, MSc, PhD, FRCP.

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Basu, B., Sandhu, S.K. & de Bono, J.S. PARP Inhibitors. Drugs 72, 1579–1590 (2012). https://doi.org/10.2165/11635510-000000000-00000

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