A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair.
Cancer cells frequently harbor defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis but also provides a weakness in the tumor that can be exploited therapeutically. Tumors with compromised ability to repair double-strand DNA breaks by homologous recombination, including those with defects in BRCA1 and BRCA2, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase. This provides the basis for a novel synthetic lethal approach to cancer therapy.
Ashworth
Alan
A
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. alan.ashworth@icr.ac.uk
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011995:Recombination, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases