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

  • An Addendum to this article was published on 17 May 2007

Abstract

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage1,2,3. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours4. 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.

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Acknowledgements

We wish to thank J. Lunec, J. Thacker, L. Thompson, M. Zdzienicka, Z. Hostomsky and Pfizer GRD, La Jolla for providing materials. The investigation was financed by grants to T.H. and M.M from Yorkshire Cancer Research. Additional support was financed through grants to T.H. from the Swedish Cancer Society and the Swedish Research Council and a grant to N.J.C. from Cancer Research-UK.

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Competing interests

The authors declare that they have no competing financial interests.

Correspondence to Thomas Helleday.

Supplementary information

Supplementary Figure S1

HR deficient cells are hypersensitive to the toxic effect caused by inhibition of PARP-1. (DOC 72 kb)

Supplementary Figure S2

Description: PARP inhibition by NU1025 and AG14361 in BRCA2 deficient cells. (DOC 52 kb)

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Further reading

Figure 1: BRCA2-deficient cells are hypersensitive to inhibitors of PARP.
Figure 2: PARP1 and not PARP2 is important in preventing formation of a recombinogenic lesion, causing death in the absence of BRCA2.
Figure 3: BRCA2-deficient cells fail to repair a recombination lesion formed by inhibitors of PARP.
Figure 4: Specific killing of a BRCA2 tumour after a 5-day treatment with a PARP1 inhibitor in xenografts.

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