Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

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A Nature Research Journal

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Published: 14 April 2005

Nature volume 434, pages 917–921 (14 April 2005) | Download Citation

BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination¹, and mutations in these genes predispose to breast and other cancers². Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks³. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.

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We thank Cancer Research UK, Breakthrough Breast Cancer and the Mary-Jean Mitchell Green Foundation for financial support. We thank I. Titley for help with FACS analysis, A. McCarthy and J. Williamson for help with chromosome spreads, E. Witt for western blot analysis, E. Iorns for real-time PCR analysis and M. Zdzienicka for V-C8 and V-C8 BAC cells. We also thank the Maybridge Chemical Company for their help in the design and synthesis of the PARP inhibitors.

These authors contributed equally to this work

Present address: Division of Experimental Oncology1, CRO-IRCCS, Aviano 33081 PN, Italy

G.C.M.S., N.M.B.M., I.H., C.K. and K.J.D. are employees of KuDOS Pharmaceuticals Ltd. S.P.J. is the scientific founder and Chief Scientific Officer of KuDOS Pharmaceuticals Ltd. A patent application has been submitted by KuDOS and the Institute of Cancer Research based on these results.

Correspondence to Graeme C. M. Smith or Alan Ashworth.

Supplementary Figure S1 describes the novel PARP inhibitor compounds used in this study. Supplementary Figure S2 shows a clonogenic experiment illustrating the rapid and irreversible effects of PARP inhibitors. Supplementary Figure S3 describes clonogenic experiments using Chinese Hamster Ovary and MCF7 cells and PARP inhibitors. Supplementary Figure S4 shows metaphase spreads, γH2AX assays and Rad51 assays.

This file contains Supplementary Table S1, Supplementary Methods, Supplementary Figure Legends and additional references.

To obtain permission to re-use content from this article visit RightsLink.

14 October 2004

11 February 2005

14 April 2005

https://doi.org/10.1038/nature03445

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The discovery that BRCA1/2 mutant cells (defective in the homologous recombination pathway of DNA repair) are spectacularly sensitive to inhibition of the enzyme PARP (involved in base excision repair) suggests a new, low toxicity, approach to the treatment of women with breast cancers caused by BRCA mutations. As the PARP inhibitors have no effect on cells with functional homologous recombination, the hope is that the treatment will be specific for breast cancer cells. PARP-inhibiting chemotherapeutics may be able to make use of a ‘synthetic lethal’ effect as an alternative to conventional nonspecific cytotoxic anticancer treatments.

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