Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer.
Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates DNA single-strand break-base excision repair to maintain genomic stability. Inhibition or loss of PARP activity leads to a recombinogenic phenotype characterized by increased sister chromatid exchange. Deficiency in homologous recombination (HR) owing to loss of BRCA1 or BRCA2 is associated with hereditary cancers of the breast, ovary, pancreas and prostate. We investigated the therapeutic potential of PARP inhibitors in HR and BRCA2-defective cells. We exposed cells defective in the HR component XRCC3 (irs1SF) and BRCA2 (V-C8) and their parental (AA8, V79) or deficiency corrected (CXR3, V-C8+B2) cells to the PARP inhibitors NU1025 and AG14361. Mice bearing BRCA2-deficient and BRCA2-proficient tumours were treated with AG14361. All HR-defective cells were hypersensitive to normally non-cytotoxic concentrations of PARP inhibitors. Cells lacking BRCA2 were 20 times more sensitive to PARP inhibitor-induced cytotoxicity. Three out of five BRCA2-defective xenografts responded to the potent PARP inhibitor, AG14361, and one tumour regressed completely, compared with non-responses in the BRCA2-proficient tumours treated with AG14361 or any mice treated with vehicle control. Untreated PARP-1(-/-) mouse embryo fibroblasts (MEFs) accumulated more DNA double-strand breaks than did PARP-1(+/+) MEFs. We believe the underlying cytotoxic mechanism is due to PARP inhibitor-mediated suppression of repair of DNA single-strand breaks, which are converted to DNA double-strand breaks at replication. These replication-associated double-strand breaks, which are normally repaired by HR, become cytotoxic in cells defective in HR. Using a DNA repair inhibitor alone to selectively kill a tumour represents an exciting new concept in cancer therapy.
Kyle
S
S
Newcastle University, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne NE2 DHH, UK.
Thomas
H D
HD
Mitchell
J
J
Curtin
N J
NJ
D000818:Animals; D052176:Azulenes / Q000627:therapeutic use; D024682:BRCA2 Protein / Q000172:deficiency / Q000187:drug effects*; D001569:Benzodiazepines / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000627:therapeutic use; D011995:Recombination, Genetic / Q000187:drug effects*
C479234:1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one; D052176:Azulenes; D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D004791:Enzyme Inhibitors; C115774:NU 1025; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D001569:Benzodiazepines