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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,6,10]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">\n                      Brca2\n                      <jats:sup>\u0394\/\u0394<\/jats:sup>\n                    <\/jats:italic>\n                    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 (\n                    <jats:italic toggle=\"yes\">Cdt1, Cdc6,<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Dbf4<\/jats:italic>\n                    ) 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\n                    <jats:italic toggle=\"yes\">\n                      Brca2\n                      <jats:sup>\u0394\/\u0394<\/jats:sup>\n                    <\/jats:italic>\n                    , 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\n                    <jats:italic toggle=\"yes\">CDT1<\/jats:italic>\n                    . 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2426743122","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T13:38:28Z","timestamp":1748957908000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":20,"title":["BRCA2 reversion mutation\u2013independent resistance to PARP inhibition through impaired DNA prereplication complex function"],"prefix":"10.1073","volume":"122","author":[{"given":"Kyrie","family":"Pappas","sequence":"first","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perianne","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Cancer Biology, University of Minnesota","place":["Minneapolis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhiksha","family":"Nandakumar","sequence":"additional","affiliation":[{"name":"Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"The Halvorsen Center for Computational Oncology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Khan","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serina B.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Columbia University Irving Medical Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"LaClair","sequence":"additional","affiliation":[{"name":"Albany Medical College","place":["Albany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco Vincenzo","family":"Russo","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami","place":["Miami"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmet","family":"Huang-Hobbs","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Schultz","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"The Halvorsen Center for Computational Oncology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wassim","family":"Abida","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"Karthaus","sequence":"additional","affiliation":[{"name":"Swiss Institute for Experimental Cancer Research, The \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne","place":["Lausanne, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7976-2379","authenticated-orcid":false,"given":"Maria","family":"Jasin","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4955-6475","authenticated-orcid":false,"given":"Charles","family":"L. 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