{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:05:41Z","timestamp":1789567541400,"version":"build-2803163510"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    PARP inhibitors have become an integral component of treatment strategies for advanced epithelial ovarian cancer, particularly in\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    -mutated and homologous recombination-deficient (HRD) tumors. Despite clinically meaningful improvements in progression-free survival, a substantial proportion of patients develop primary or acquired resistance, ultimately limiting the long-term efficacy of these agents. Increasing evidence indicates that resistance to PARP inhibition is a biologically heterogeneous process involving restoration of homologous recombination (HR) through\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    reversion mutations, replication fork stabilization, alterations in\n                    <jats:italic>PARP1<\/jats:italic>\n                    function, epigenetic reprogramming, drug efflux mechanisms, and adaptive changes in DNA damage response pathways. In parallel, intratumoral heterogeneity and tumor microenvironment remodeling may further contribute to therapeutic failure and clonal selection under treatment pressure. The growing complexity of resistance biology has highlighted the limitations of static genomic biomarkers and has stimulated interest in dynamic molecular profiling approaches, including circulating tumor DNA analysis and functional assays evaluating homologous recombination proficiency (HRP). Several therapeutic strategies are currently being investigated to overcome PARP inhibitor resistance, including combinations with antiangiogenic agents, immune checkpoint inhibitors,\n                    <jats:italic>ATR<\/jats:italic>\n                    ,\n                    <jats:italic>WEE1<\/jats:italic>\n                    and\n                    <jats:italic>CHK1<\/jats:italic>\n                    inhibitors, antibody-drug conjugates, and epigenetic therapies. This narrative review summarizes the current understanding of the molecular mechanisms underlying resistance to PARP inhibitors in advanced epithelial ovarian cancer and discusses their potential therapeutic implications, with particular emphasis on biomarker-driven treatment strategies and translational approaches aimed at improving patient selection and long-term disease control.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1892991","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:20:11Z","timestamp":1789564811000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms of resistance to PARP inhibitors in advanced epithelial ovarian cancer: biological determinants and therapeutic implications"],"prefix":"10.3389","volume":"16","author":[{"given":"Dalila","family":"Incognito","sequence":"first","affiliation":[{"name":"Medical Oncology Unit, Department of Human Pathology \u201cG. 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Barresi\u201d, School of Specialization in Medical Oncology, University of Messina","place":["Messina, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina","place":["Messina, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"D\u2019Arienzo","sequence":"additional","affiliation":[{"name":"Oncology Unit, S. Maria Delle Grazie Hospital","place":["Pozzuoli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Barraco","sequence":"additional","affiliation":[{"name":"Oncology Unit, S. 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