Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
| Autor: | Elena Lopez, Suzanne Kyle, Mark Meuth, Nicola J. Curtin, Nilklas Schultz, Dan Flower, Huw D. Thomas, Helen E. Bryant, Kayan M. Parker, Thomas Helleday |
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| Rok vydání: | 2005 |
| Předmět: |
DNA Replication
DNA Repair DNA repair DNA Repair Inhibition Genes BRCA2 RAD51 Mice Nude Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors Poly (ADP-Ribose) Polymerase Inhibitor Azulenes Benzodiazepines Mice PARP1 Cell Line Tumor Neoplasms Animals BRCA2 Protein Multidisciplinary Chemistry Xenograft Model Antitumor Assays Molecular biology Homologous Recombination Pathway PARP inhibitor Poly(ADP-ribose) Polymerases Homologous recombination DNA Damage |
| Zdroj: | Nature. 434:913-917 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature03443 |
| Popis: | 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 gamma-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. |
| Databáze: | OpenAIRE |
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