title: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
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 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.
authors.affiliation: The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Bryant
authors.forename: Niklas
authors.initials: N
authors.lastname: Schultz
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.forename: Kayan M
authors.initials: KM
authors.lastname: Parker
authors.forename: Dan
authors.initials: D
authors.lastname: Flower
authors.forename: Elena
authors.initials: E
authors.lastname: Lopez
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kyle
authors.forename: Mark
authors.initials: M
authors.lastname: Meuth
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D052176:Azulenes; D024682:BRCA2 Protein / Q000172:deficiency* / Q000235:genetics; D001569:Benzodiazepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D024522:Genes, BRCA2; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C479234:1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one; D000970:Antineoplastic Agents; D052176:Azulenes; D024682:BRCA2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D001569:Benzodiazepines; D011065:Poly(ADP-ribose) Polymerases