Molecular Pathways: How can BRCA-mutated tumors become resistant to PARP inhibitors?
Cet article passe en revue les travaux récents sur les mécanismes de résistance aux inhibiteurs de PARP dans les tumeurs présentant des mutations du gène BRCA1 ou BRCA2
PARP inhibition is synthetic lethal with defective DNA repair via homologous recombination. Phase 1 and 2 clinical trials show that PARP inhibitors are effective at well-tolerated doses and have anti-tumor 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.