Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
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.
Bryant
Helen E
HE
The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
Schultz
Niklas
N
Thomas
Huw D
HD
Parker
Kayan M
KM
Flower
Dan
D
Lopez
Elena
E
Kyle
Suzanne
S
Meuth
Mark
M
Curtin
Nicola J
NJ
Helleday
Thomas
T
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
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