Originally published as JCO Early Release 10.1200/JCO.2008.16.0812 on June 30 2008

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A Synthetic Lethal Therapeutic Approach: Poly(ADP) Ribose Polymerase Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair

Alan Ashworth

From the Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom

Corresponding author: Alan Ashworth, MD, the Institute of Cancer Research, 237 Fulham Rd, London, SW3 6JB, United Kingdom; e-mail: alan.ashworth{at}icr.ac.uk

Cancer cells frequently harbor defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis but also provides a weakness in the tumor that can be exploited therapeutically. Tumors with compromised ability to repair double-strand DNA breaks by homologous recombination, including those with defects in BRCA1 and BRCA2, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase. This provides the basis for a novel synthetic lethal approach to cancer therapy.

published online ahead of print at www.jco.org on June 30, 2008.

Supported by Cancer Research UK and Breakthrough Breast Cancer.

Disclaimer: A.A. is a named co-inventor on patents relating to the use of PARP inhibitors and may benefit financially under the Institute of Cancer Research Rewards to Inventors scheme.

Author's disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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