Inactivating mutations in BRCA1 or BRCA2 genes predispose to several types of cancer. Owing to their roles in maintaining genomic stability, lack of BRCA1/2 results in DNA damage repair defects, a... Show moreInactivating mutations in BRCA1 or BRCA2 genes predispose to several types of cancer. Owing to their roles in maintaining genomic stability, lack of BRCA1/2 results in DNA damage repair defects, a vulnerability that can be exploited therapeutically by the inhibition of poly(ADPribose) polymerase 1 (PARP1). Unfortunately, clinical benefit of PARPi therapy is often limited by emerging drug resistance. Identification of PARPi resistance mechanisms is therefore crucial to improve the clinical outcome and design strategies that would ultimately prevent or target resistant tumors.The use of genetically engineered mouse models (GEMMs) of BRCA1/2-associated breastcancer in this work has allowed us to model PARPi resistance in vivo in well-defined genetic contexts. By combining high-throughput genetic screens, multiple omics analyses and functional assays, we identified several factors of PARPi resistance and explained their role in therapy failure. Moreover, we established a new tumor-derived organoid system thatenables robust in vivo validation of putative drug resistance factors. Finally, work described in this thesis has advanced our understanding of basic biological processes involved in DNA damage signaling and repair. Show less
