Molecular pathways: How can BRCA-mutated tumors become resistant to PARP inhibitors?

Abstract

PARP inhibition is synthetic lethal with defectiveDNArepair 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 theDNAdamage 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. © 2014 American Association for Cancer Research.