{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:44:20Z","timestamp":1775108660233,"version":"3.50.1"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008061","name":"Fundaci\u00f3n Mutua Madrile\u00f1a","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019717","name":"AstraZeneca Espa\u00f1a","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019717","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      High-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) frequently exhibit mutations in DNA damage response (DDR) genes, as\n                      <jats:italic>BRCA1, BRCA2<\/jats:italic>\n                      and\n                      <jats:italic>TP53<\/jats:italic>\n                      , which are associated with chemotherapy sensitivity. Olaparib, a PARP inhibitor, provides the greatest clinical benefit as maintenance therapy in HGSOC\u2014particularly in tumors with BRCA1\/2 mutations or broader homologous recombination deficiency (HRD)\u2014whereas benefit in HRD\u2212negative disease is limited. Eprenetapopt (APR-246) restores wild-type p53 function in tumor cells with\n                      <jats:italic>TP53<\/jats:italic>\n                      mutations. This study investigates the potential of combining eprenetapopt with carboplatin to overcome resistance to the PARP inhibitor (PARPi) olaparib in HGSOC and TNBC cell lines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>As preclinical models, human ovarian cancer cell lines (HGSOC) (PEO1, Kuramochi) and a triple-negative breast cancer cell line (MDA-MB-231) were utilized as parental lines to generate their respective olaparib-resistant cell lines (PEO1R, Kuramochi-R, MDA-MB-231-R) by exposing the cells to increasing doses of olaparib. Cell viability, apoptosis and cell cycle progression, were assessed using MTT assays and Annexin V assay and propidium iodide staining, respectively. The Chou-Talalay method was used to calculate the combination index (CI) for drug synergism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Olaparib-resistance was confirmed in both HGSOC and TNBC cell lines, as they exhibited significantly higher IC\n                      <jats:sub>50<\/jats:sub>\n                      values compared to their respective parental lines. Moreover, the olaparib-resistant cells exhibited cross-resistance to carboplatin. Remarkably, the combination of eprenetapopt with carboplatin showed a synergistic effect in both parental and resistant cell lines, reducing tumor cell viability and demonstrating synergistic interaction compared with single agents. Combinatorial treatment also significantly increased apoptotic cell population in parental HGSOC and TNBC cell lines as well as in MDA-MB-231-R olaparib-resistant cells. Cell cycle analysis revealed that carboplatin mainly induced a significant increase in S or G2\/M phase accumulation and a reduction in G1-phase cells, with eprenetapopt having a minimal additional impact.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Combining eprenetapopt with carboplatin shows promising preclinical efficacy by enhancing cytotoxicity in olaparib\u2212resistant models and demonstrating synergistic interaction; these data support the combination as a potential strategy to mitigate PARPi resistance and carboplatin cross\u2212resistance in\n                      <jats:italic>TP53<\/jats:italic>\n                      mutant HGSOC and TNBC cell lines. Although further studies are needed to elucidate the molecular mechanisms underlying the synergistic effect, here we point out the combination of eprenetapopt and carboplatin as a potential therapeutic strategy to address olaparib resistance in HGSOC and TNBC patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1754873","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:19:12Z","timestamp":1775103552000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Eprenetapopt in combination with carboplatin in high-grade ovarian and triple negative breast cancer cell lines with acquired resistance to olaparib"],"prefix":"10.3389","volume":"16","author":[{"given":"Bego\u00f1a","family":"Pineda","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Odontology, University of Valencia","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Jose","family":"Martinez-Pretel","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute (INCLIVA)","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paloma","family":"Sanchez- Serrano","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute (INCLIVA)","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stergios","family":"Boussios","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, School of Health Sciences, University of Ioannina","place":["Ioannina, Greece"]},{"name":"Department of Medical Oncology, University Hospital of Ioannina","place":["Ioannina, Greece"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Rodrigo-Faus","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute (INCLIVA)","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mart\u00edn","family":"P\u00e9rez-Leal","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Universidad Europea de Valencia","place":["Valencia, Spain"]},{"name":"Centro Avanzado de Microbiolog\u00eda Aplicada, Universitat Polit\u00e8cnica de Val\u00e8ncia","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Obrador","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Odontology, University of Valencia","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Perea","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute (INCLIVA)","place":["Valencia, Spain"]},{"name":"Department of Medical Oncology, Hospital Clinico Universitario de Valencia","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Alejandro","family":"Perez-Fidalgo","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute (INCLIVA)","place":["Valencia, Spain"]},{"name":"Department of Medical Oncology, Hospital Clinico Universitario de Valencia","place":["Valencia, Spain"]},{"name":"Department of Medicine, University of Valencia","place":["Valencia, Spain"]},{"name":"CIBERONC","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10166","article-title":"Integrated genomic analyses of ovarian carcinoma","volume":"474","year":"2011","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/nature11412","article-title":"Comprehensive molecular portraits of human breast tumours","volume":"490","year":"2012","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11891","article-title":"Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline\/taxane-based chemotherapy","volume":"7","author":"Darb-Esfahani","year":"2016","journal-title":"Oncotarget"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s12282-023-01451-8","article-title":"Adjuvant Olaparib for patients with BRCA1- or BRCA2-mutated breast cancer","volume":"384","author":"Tutt","year":"2021","journal-title":"N Eng J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2020.38.15_suppl.6051","article-title":"Niraparib in patients with newly diagnosed advanced ovarian cancer","volume":"381","author":"Gonzalez-Martin","year":"2019","journal-title":"N Eng J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/jco.22.01003","article-title":"A randomized, phase III trial to evaluate Rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA\u2013MONO\/GOG-3020\/ENGOT-ov45)","volume":"40","author":"Monk","year":"2022","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1911361","article-title":"Olaparib plus bevacizumab as first line maintenance in ovarian cancer","volume":"381","author":"Ray-Cocquard","year":"2019","journal-title":"N Eng J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-024-03531-3","article-title":"SEOM-GEICO clinical guideline on epithelial ovarian cancer (2023)","volume":"26","author":"Perez-Fidalgo","year":"2024","journal-title":"Clin Transl Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026104","article-title":"The cell-cycle arrest and apoptotic functions of P53 in tumor initiation and progression","volume":"6","author":"Chen","year":"2016","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/s41698-022-00303-6","article-title":"Impact of TP53 mutations in triple negative breast cancer","volume":"6","author":"Mitri","year":"2022","journal-title":"NPJ Precis Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.02342","article-title":"Eprenetapopt plus azacitidne in TP53.mutant myelodysplastic syndromes and acute myeloid leukemia: a phase II study in the group francophone des myelodysplasies (GFM)","volume":"39","author":"Cluzeau","year":"2021","journal-title":"J Clin Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.143","article-title":"APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells","volume":"6","author":"Mohell","year":"2015","journal-title":"Cell Death Dis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2016.34.15_suppl.5571","article-title":"PISARRO: A EUTROC phase Ib study of APR-246 in combination with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in platinum sensitive relapsed high grade serous ovarian cancer (HGSOC)","volume":"34","author":"Gourley","year":"2016","journal-title":"J Clin Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-09-1947","article-title":"Drug combination studies and their synergy quantification using a Chou-Talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1981.tb06218.x","article-title":"Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors","volume":"115","author":"Chou","year":"1981","journal-title":"Eur J Biochem"},{"key":"B16","volume-title":"FlowJo\u2122 Software (for Windows) [software application] Version v10.8","year":"2023"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-4121","article-title":"EVOLVE: A multicenter open-label single-arm clinical and translational phase II trial of Cediranib plus Olaparib for ovarian cancer after PARP inhibition progression","volume":"26","author":"Lhereux","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-18-0715","article-title":"BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor Rucaparib in high-grade ovarian carcinoma","volume":"9","author":"Lin","year":"2019","journal-title":"Cancer Disc"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.06.011","article-title":"Efficacy of subsequent chemotherapy for patients with BRCA1\/2-mutated recurrent epithelial ovarian cancer progressing on Olaparib versus placebo maintenance: post-hoc analyses of the SOLO2\/ENGOT Ov-21 trial","volume":"33","author":"Frenel","year":"2022","journal-title":"Ann Oncol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"suppl_5550","DOI":"10.1200\/jco.2023.41.16_suppl.5550","article-title":"Efficacy of subsequent therapies in patients with advanced ovarian cancer in the phase III PAOLA-1\/ENGOT-ov25 trial according to whether disease progression occurred during or after the end of Olaparib maintenance","volume":"41","author":"Harter","year":"2023","journal-title":"J Clin Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02491-8","article-title":"Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer","volume":"41","author":"Huang","year":"2022","journal-title":"Oncogene"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1754873\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:19:14Z","timestamp":1775103554000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1754873\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":21,"alternative-id":["10.3389\/fonc.2026.1754873"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1754873","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,2]]},"article-number":"1754873"}}