{"doi":"10.1073/pnas.2426743122","title":"BRCA2 reversion mutation–independent resistance to PARP inhibition through impaired DNA prereplication complex function","abstract":"Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify genomic determinants of PARPi resistance in murine Brca2 Δ/Δ prostate organoids genetically engineered in a manner that precludes the development of reversion mutations. Remarkably, we recovered multiple independent single guide RNAs (sgRNAs) targeting three different members ( Cdt1, Cdc6, and Dbf4 ) of the DNA prereplication complex (pre-RC), each of which independently conferred resistance to olaparib and the next-generation PARP-1 selective inhibitor AZD5305. Moreover, sensitivity to PARP inhibition was restored in Brca2 Δ/Δ , Cdc6-depleted prostate cells by knockdown of geminin, a negative regulator of Cdt1, further implicating the critical role of a functional pre-RC complex in PARPi sensitivity. Furthermore, ~50% of CRPC tumors have copy number loss of pre-RC complex genes, particularly CDT1 . Mechanistically, prostate cells with impaired pre-RC activity displayed rapid resolution of olaparib-induced DNA damage as well as protection from replication fork degradation caused by Brca2 loss, providing insight into how Brca2-mutant cancer cells can escape cell death from replication stress induced by PARP inhibition in the absence of HR repair. Of note, a pharmacologic inhibitor that targets the CDT1/geminin complex (AF615) restored sensitivity to AZD5305, providing a potential translational avenue to enhance sensitivity to PARP inhibition.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":513390,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1374441,"name":"Matteo Ferrari","orcid":"0000-0001-6672-3170","position":1,"is_corresponding":false},{"id":1375144,"name":"Perianne Smith","orcid":null,"position":2,"is_corresponding":false},{"id":294444,"name":"Subhiksha Nandakumar","orcid":"0000-0003-0258-3484","position":3,"is_corresponding":false},{"id":649130,"name":"Zahra Khan","orcid":null,"position":4,"is_corresponding":false},{"id":1375145,"name":"Serina B Young","orcid":null,"position":5,"is_corresponding":false},{"id":882597,"name":"Justin LaClair","orcid":null,"position":6,"is_corresponding":false},{"id":1213807,"name":"Marco Vincenzo Russo","orcid":"0000-0002-5148-1305","position":7,"is_corresponding":false},{"id":323662,"name":"Emmet Huang-Hobbs","orcid":"0000-0002-2071-2588","position":8,"is_corresponding":false},{"id":1863,"name":"Nikolaus Schultz","orcid":"0000-0002-0131-4904","position":9,"is_corresponding":false},{"id":50783,"name":"Wassim Abida","orcid":"0000-0002-9006-7043","position":10,"is_corresponding":false},{"id":50776,"name":"Wouter R. 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