title: Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors?
abstract: PARP inhibition is synthetic lethal with defective DNA repair via homologous recombination. Phase I and II clinical trials show that PARP inhibitors are effective at well-tolerated doses and have antitumor activity for BRCA1- and BRCA2-associated cancers. However, not all patients respond equally well and tumors may eventually become resistant. Thus far, the only resistance mechanism that has been found in human tumors is genetic reversion that corrects or bypasses the original BRCA1- or BRCA2-inactivating mutation. However, data from fundamental and preclinical research suggest that resistance to PARP inhibitors may be induced by additional mechanisms involving hypomorphic activity of mutant BRCA1 alleles, upregulation of drug efflux pumps, and rewiring of the DNA damage response. Preclinical models will be instrumental to develop methods for adequate patient stratification, as well as treatment strategies that prevent or counteract resistance to PARP inhibitors.
authors.affiliation: Authors' Affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors