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Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

Lookup NU author(s): Huw ThomasORCiD, Kathleen Parker, Suzanne Kyle, Professor Nicola CurtinORCiD

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Abstract

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger γ-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.

Publication metadata

Author(s): Bryant H, Schultz N, Thomas HD, Parker K, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2005

Volume: 434

Issue: 7035

Pages: 913-917

Print publication date: 14/04/2005

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

URL: http://dx.doi.org/10.1038/nature03443

DOI: 10.1038/nature03443

PubMed id: 15829966

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