{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:05:24Z","timestamp":1781625924916,"version":"3.54.5"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":34,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC","doi-asserted-by":"crossref","award":["IG22835"],"award-info":[{"award-number":["IG22835"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100020581","name":"Fondazione AIRC","doi-asserted-by":"crossref","award":["MFAG 2023 ID. 28919"],"award-info":[{"award-number":["MFAG 2023 ID. 28919"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The antineoplastic agents, Poly ADP-ribose polymerase (PARP) inhibitors (PARPi) and platinum-based drugs, marked a paradigm shifting in high-grade serous ovarian cancer (HG-SOC) treatment. Nonetheless, the HG-SOC vulnerability to these agents is challenged by the hyper-activation of adaptive pro-survival pathways. In this study, we report that the endothelin A receptor (ET\n                    <jats:sub>A<\/jats:sub>\n                    R), whose overexpression correlated with an unfavourable HG-SOC patient outcomes, predicted a worst prognosis in the homologous recombination proficient subgroup of patients. ET\n                    <jats:sub>A<\/jats:sub>\n                    R levels increased upon treatment with DNA damaging agents, as the PARPi olaparib, or cisplatin in patient-derived (PD) HG-SOC cells and HG-SOC cell lines, regardless of their\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    mutational status. Mechanistically, these compounds, inducing the DNA Damage Response (DDR) signalling, including ATM and ATR, leveraged the STAT3-dependent transcriptional machinery to induce ET\n                    <jats:sub>A<\/jats:sub>\n                    R expression. The genetic and pharmacological inhibition of ET\n                    <jats:sub>A<\/jats:sub>\n                    R has the ability to potentiate the efficacy of the PARPi with DDR inhibitors (DDRi) combination, blocking the ET\n                    <jats:sub>A<\/jats:sub>\n                    R-mediated evasion from PARPi-induced apoptosis and DNA damage. Clinically relevant, in PD HG-SOC xenografts, the co-targeting of PARP, ATR, and ET\n                    <jats:sub>A<\/jats:sub>\n                    R effectively suppressed the olaparib-induced ET\n                    <jats:sub>A<\/jats:sub>\n                    R upregulation and enhanced PARPi sensitivity, preventing metastatic dissemination. These results explain a resilience mechanism in which ET\n                    <jats:sub>A<\/jats:sub>\n                    R confers a therapeutic vulnerability that may be leveraged for therapy with ATR and ET\n                    <jats:sub>A<\/jats:sub>\n                    R inhibitors in combination with PARPi, holding the promise of developing new therapeutic strategies less prone to drug resistance.\n                  <\/jats:p>","DOI":"10.1186\/s13046-025-03607-0","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T03:45:29Z","timestamp":1764992729000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DNA damaging agents boost the transcription of endothelin A receptor in high-grade serous ovarian cancer"],"prefix":"10.1186","volume":"45","author":[{"given":"Celia","family":"Roman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Sestito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Caprara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sacconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Blandino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bagnato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piera","family":"Tocci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,6]]},"reference":[{"key":"3607_CR1","doi-asserted-by":"publisher","first-page":"952","DOI":"10.3390\/ijms20040952","volume":"20","author":"MA Lisio","year":"2019","unstructured":"Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-grade serous ovarian cancer: basic sciences, clinical and therapeutic standpoints. Int J Mol Sci. 2019;20:952.","journal-title":"Int J Mol Sci"},{"key":"3607_CR2","doi-asserted-by":"publisher","first-page":"1556377","DOI":"10.3389\/fimmu.2025.1556377","volume":"16","author":"R Fu","year":"2025","unstructured":"Fu R, Hu R, Li W, Lv X, Zhao H, Li F. Unveiling drug resistance pathways in high-grade serous ovarian cancer (HGSOC): recent advances and future perspectives. Front Immunol. 2025;16:1556377.","journal-title":"Front Immunol"},{"key":"3607_CR3","doi-asserted-by":"publisher","first-page":"e174013","DOI":"10.1172\/JCI174013","volume":"134","author":"Y Wang","year":"2024","unstructured":"Wang Y, Duval AJ, Adli M, Matei D. Biology-driven therapy advances in high-grade serous ovarian cancer. J Clin Invest. 2024;134:e174013.","journal-title":"J Clin Invest"},{"key":"3607_CR4","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41571-021-00532-x","volume":"18","author":"MP Dias","year":"2021","unstructured":"Dias MP, Moser SC, Ganesan S, Jonkers J. Understanding and overcoming resistance to PARP inhibitors in cancer therapy. Nat Rev Clin Oncol. 2021;18:773\u201391.","journal-title":"Nat Rev Clin Oncol"},{"key":"3607_CR5","doi-asserted-by":"publisher","first-page":"175883592311576","DOI":"10.1177\/17588359231157644","volume":"15","author":"AC Veneziani","year":"2023","unstructured":"Veneziani AC, Scott C, Wakefield MJ, Tinker AV, Lheureux S. Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer. Ther Adv Med Oncol. 2023;15:17588359231157644.","journal-title":"Ther Adv Med Oncol"},{"key":"3607_CR6","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1007\/s40265-023-01934-0","volume":"83","author":"V Garg","year":"2023","unstructured":"Garg V, Oza AM. Treatment of ovarian cancer beyond PARP inhibition: current and future options. Drugs. 2023;83:1365\u201385.","journal-title":"Drugs"},{"key":"3607_CR7","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.gendis.2023.02.014","volume":"11","author":"X Fu","year":"2023","unstructured":"Fu X, Li P, Zhou Q, He R, Wang G, Zhu S, et al. Mechanism of PARP inhibitor resistance and potential overcoming strategies. Genes Dis. 2023;11:306\u201320.","journal-title":"Genes Dis"},{"key":"3607_CR8","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nrc3546","volume":"13","author":"L Rosan\u00f2","year":"2013","unstructured":"Rosan\u00f2 L, Spinella F, Bagnato A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2013;13:637\u201351.","journal-title":"Nat Rev Cancer"},{"key":"3607_CR9","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1158\/1078-0432.CCR-10-2325","volume":"17","author":"L Rosan\u00f2","year":"2011","unstructured":"Rosan\u00f2 L, Cianfrocca R, Spinella F, Di Castro V, Nicotra MR, Lucidi A, et al. Acquisition of chemoresistance and EMT phenotype is linked with activation of the endothelin A receptor pathway in ovarian carcinoma cells. Clin Cancer Res. 2011;17:2350\u201360.","journal-title":"Clin Cancer Res"},{"key":"3607_CR10","doi-asserted-by":"publisher","first-page":"7453","DOI":"10.1158\/0008-5472.CAN-13-3133","volume":"74","author":"L Rosan\u00f2","year":"2014","unstructured":"Rosan\u00f2 L, Cianfrocca R, Tocci P, Spinella F, Di Castro V, Caprara V, et al. Endothelin A receptor\/\u03b2-arrestin signaling to the Wnt pathway renders ovarian cancer cells resistant to chemotherapy. Cancer Res. 2014;74:7453\u201364.","journal-title":"Cancer Res"},{"key":"3607_CR11","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.1038\/s41467-019-11045-8","volume":"10","author":"P Tocci","year":"2019","unstructured":"Tocci P, Cianfrocca R, Di Castro V, Rosan\u00f2 L, Sacconi A, Donzelli S, et al. \u03b2-arrestin1\/YAP\/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer. Nat Commun. 2019;10:3196.","journal-title":"Nat Commun"},{"key":"3607_CR12","doi-asserted-by":"publisher","first-page":"2885","DOI":"10.1016\/j.cellsig.2014.08.024","volume":"26","author":"JP Teoh","year":"2014","unstructured":"Teoh JP, Park KM, Wang Y, Hu Q, Kim S, Wu G, et al. Endothelin-1\/endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis. Cell Signal. 2014;26:2885\u201395.","journal-title":"Cell Signal"},{"key":"3607_CR13","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/S0026-895X(24)12115-3","volume":"61","author":"D Del Bufalo","year":"2002","unstructured":"Del Bufalo D, Di Castro V, Biroccio A, Varmi M, Salani D, Rosan\u00f2 L, et al. Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. Mol Pharmacol. 2002;61:524\u201332.","journal-title":"Mol Pharmacol"},{"key":"3607_CR14","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41419-022-05538-6","volume":"14","author":"P Tocci","year":"2023","unstructured":"Tocci P, Roman C, Sestito R, Di Castro V, Sacconi A, Molineris I, et al. Targeting tumor-stroma communication by blocking endothelin-1 receptors sensitizes high-grade serous ovarian cancer to PARP Inhibition. Cell Death Dis. 2023;14:5.","journal-title":"Cell Death Dis"},{"key":"3607_CR15","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1042\/CS20240346","volume":"138","author":"P Tocci","year":"2024","unstructured":"Tocci P, Roman C, Sestito R, Caprara V, Sacconi A, Molineris I, et al. The endothelin-1-driven tumor-stroma feed-forward loops in high-grade serous ovarian cancer. Clin Sci (Lond). 2024;138:851\u201362.","journal-title":"Clin Sci (Lond)"},{"key":"3607_CR16","doi-asserted-by":"publisher","first-page":"429","DOI":"10.2174\/1381612826666200115095937","volume":"26","author":"S Nisar","year":"2020","unstructured":"Nisar S, Hashem S, Macha MA, Yadav SK, Muralitharan S, Therachiyil L, et al. Exploring dysregulated signaling pathways in cancer. Curr Pharm Des. 2020;26:429\u201345.","journal-title":"Curr Pharm Des"},{"key":"3607_CR17","doi-asserted-by":"publisher","first-page":"3711","DOI":"10.1158\/1078-0432.CCR-16-3215","volume":"23","author":"S Jiao","year":"2017","unstructured":"Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23:3711\u201320.","journal-title":"Clin Cancer Res"},{"key":"3607_CR18","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1038\/s41467-017-01883-9","volume":"8","author":"H Sato","year":"2017","unstructured":"Sato H, Niimi A, Yasuhara T, Permata TBM, Hagiwara Y, Isono M, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun. 2017;8:1751.","journal-title":"Nat Commun"},{"key":"3607_CR19","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1158\/2159-8290.CD-18-1020","volume":"9","author":"T Sen","year":"2019","unstructured":"Sen T, Rodriguez BL, Chen L, Corte CMD, Morikawa N, Fujimoto J, et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 2019;9:646\u201361.","journal-title":"Cancer Discov"},{"key":"3607_CR20","doi-asserted-by":"publisher","first-page":"762989","DOI":"10.3389\/fimmu.2021.762989","volume":"12","author":"Y Wang","year":"2021","unstructured":"Wang Y, Zheng K, Xiong H, Huang Y, Chen X, Zhou Y, et al. PARP inhibitor upregulates PD-L1 expression and provides a new combination therapy in pancreatic cancer. Front Immunol. 2021;12:762989.","journal-title":"Front Immunol"},{"key":"3607_CR21","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1111\/jcmm.17802","volume":"27","author":"L Chi","year":"2023","unstructured":"Chi L, Huan L, Zhang C, Wang H, Lu J. Adenosine receptor A2b confers ovarian cancer survival and PARP inhibitor resistance through IL-6-STAT3 signalling. J Cell Mol Med. 2023;27:2150\u201364.","journal-title":"J Cell Mol Med"},{"key":"3607_CR22","doi-asserted-by":"publisher","first-page":"3811","DOI":"10.1002\/1878-0261.13224","volume":"16","author":"JS Baxter","year":"2022","unstructured":"Baxter JS, Zatreanu D, Pettitt SJ, Lord CJ. Resistance to DNA repair inhibitors in cancer. Mol Oncol. 2022;16:3811\u201327.","journal-title":"Mol Oncol"},{"key":"3607_CR23","doi-asserted-by":"publisher","first-page":"103830","DOI":"10.1016\/j.dnarep.2025.103830","volume":"149","author":"S Kulkarni","year":"2025","unstructured":"Kulkarni S, Seneviratne N, Tosun \u00c7, Madhusudan S. PARP inhibitors in ovarian cancer: mechanisms of resistance and implications to therapy. DNA Repair (Amst). 2025;149:103830.","journal-title":"DNA Repair (Amst)"},{"key":"3607_CR24","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","volume":"70","author":"TC Chou","year":"2010","unstructured":"Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440\u201346.","journal-title":"Cancer Res"},{"key":"3607_CR25","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1158\/2159-8290.CD-15-0714","volume":"5","author":"PA Konstantinopoulos","year":"2015","unstructured":"Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D\u2019Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5:1137\u201354.","journal-title":"Cancer Discov"},{"key":"3607_CR26","doi-asserted-by":"publisher","first-page":"1387281","DOI":"10.3389\/fonc.2024.1387281","volume":"14","author":"N Stiegeler","year":"2024","unstructured":"Stiegeler N, Garsed DW, Au-Yeung G, Bowtell DDL, Heinzelmann-Schwarz V, Zwimpfer TA. Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group. Front Oncol. 2024;14:1387281.","journal-title":"Front Oncol"},{"key":"3607_CR27","doi-asserted-by":"publisher","first-page":"772604","DOI":"10.3389\/fonc.2021.772604","volume":"11","author":"M Zhang","year":"2021","unstructured":"Zhang M, Ma SC, Tan JL, Wang J, Bai X, Dong ZY, et al. Inferring homologous recombination deficiency of ovarian cancer from the landscape of copy number variation at subchromosomal and genetic resolutions. Front Oncol. 2021;11:772604.","journal-title":"Front Oncol"},{"key":"3607_CR28","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.annonc.2021.02.015","volume":"32","author":"T Baert","year":"2021","unstructured":"Baert T, Ferrero A, Sehouli J, O\u2019Donnell DM, Gonz\u00e1lez-Mart\u00edn A, Joly F, et al. The systemic treatment of recurrent ovarian cancer revisited. Ann Oncol. 2021;32:710\u201325.","journal-title":"Ann Oncol"},{"key":"3607_CR29","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.pbiomolbio.2020.11.005","volume":"161","author":"RM Williams","year":"2021","unstructured":"Williams RM, Zhang X. Roles of ATM and ATR in DNA double strand breaks and replication stress. Prog Biophys Mol Biol. 2021;161:27\u201338.","journal-title":"Prog Biophys Mol Biol"},{"key":"3607_CR30","doi-asserted-by":"publisher","first-page":"200934","DOI":"10.1016\/j.omton.2025.200934","volume":"33","author":"X Lin","year":"2025","unstructured":"Lin X, Qiu Y, Soni A, Stuschke M, Iliakis G. Reversing regulatory safeguards: targeting the ATR pathway to overcome PARP inhibitor resistance. Mol Ther Oncol. 2025;33:200934.","journal-title":"Mol Ther Oncol"},{"key":"3607_CR31","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3892\/ijo.2022.5461","volume":"62","author":"YJ Lee","year":"2022","unstructured":"Lee YJ, Jung E, Choi J, Hwang JS, Jeong EJ, Roh Y, et al. The EDN1\/EDNRA\/\u03b2 arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. Int J Oncol. 2022;62:13.","journal-title":"Int J Oncol"},{"key":"3607_CR32","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nature04296","volume":"439","author":"A Bild","year":"2006","unstructured":"Bild A, Yao G, Chang J, Chang JT, Wang Q, Potti A, Chasse D, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439:353\u20137.","journal-title":"Nature"},{"key":"3607_CR33","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.ebiom.2019.03.027","volume":"43","author":"J Yi","year":"2019","unstructured":"Yi J, Liu C, Tao Z, Wang M, Jia Y, Sang X, et al. MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer. EBioMedicine. 2019;43:225\u201337.","journal-title":"EBioMedicine"},{"key":"3607_CR34","doi-asserted-by":"publisher","first-page":"750","DOI":"10.3390\/genes15060750","volume":"15","author":"T Senturk Kirmizitas","year":"2024","unstructured":"Senturk Kirmizitas T, Van den Berg C, Boers R, Helmijr J, Makrodimitris S, Dag HH, et al. Epigenetic and genomic hallmarks of PARP-inhibitor resistance in ovarian cancer patients. Genes (Basel). 2024;15:750.","journal-title":"Genes (Basel)"},{"key":"3607_CR35","doi-asserted-by":"publisher","first-page":"5478","DOI":"10.7150\/thno.33444","volume":"9","author":"T Lu","year":"2019","unstructured":"Lu T, Bankhead A III, Ljungman M, Neamati N. Multi-omics profiling reveals key signaling pathways in ovarian cancer controlled by STAT3. Theranostics. 2019;9:5478\u201396.","journal-title":"Theranostics"},{"key":"3607_CR36","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.dnarep.2019.06.005","volume":"80","author":"M Mirza-Aghazadeh-Attari","year":"2019","unstructured":"Mirza-Aghazadeh-Attari M, Ostadian C, Saei AA, Mihanfar A, Darband SG, Sadighparvar S, et al. DNA damage response and repair in ovarian cancer: potential targets for therapeutic strategies. DNA Repair (Amst). 2019;80:59\u201384.","journal-title":"DNA Repair (Amst)"},{"key":"3607_CR37","doi-asserted-by":"publisher","first-page":"448","DOI":"10.3390\/cancers15020448","volume":"15","author":"M Ovejero-S\u00e1nchez","year":"2023","unstructured":"Ovejero-S\u00e1nchez M, Gonz\u00e1lez-Sarmiento R, Herrero AB. DNA damage response alterations in ovarian cancer: from molecular mechanisms to therapeutic opportunities. Cancers (Basel). 2023;15:448.","journal-title":"Cancers (Basel)"},{"key":"3607_CR38","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.3390\/biomedicines13051126","volume":"13","author":"S Apelian","year":"2025","unstructured":"Apelian S, Martincuks A, Whittum M, Yasukawa M, Nguy L, Mathyk B, et al. PARP inhibitors in ovarian cancer: resistance mechanisms, clinical evidence, and evolving strategies. Biomedicines. 2025;13:1126.","journal-title":"Biomedicines"},{"key":"3607_CR39","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1186\/s13046-019-1161-8","volume":"38","author":"M Shen","year":"2019","unstructured":"Shen M, Xu Z, Xu W, Jiang K, Zhang F, Ding Q, et al. Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK\/STAT3\/PD-L1 pathway. J Exp Clin Cancer Res. 2019;38:149.","journal-title":"J Exp Clin Cancer Res"},{"key":"3607_CR40","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1158\/1541-7786.MCR-19-0934","volume":"18","author":"A Khanna","year":"2020","unstructured":"Khanna A, Thoms JAI, Stringer BW, Chung SA, Ensbey KS, Jue TR, et al. Constitutive CHK1 expression drives a pSTAT3-CIP2A circuit that promotes glioblastoma cell survival and growth. Mol Cancer Res. 2020;18:709\u201322.","journal-title":"Mol Cancer Res"},{"key":"3607_CR41","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1158\/1541-7786.MCR-21-0366","volume":"20","author":"L Zhou","year":"2022","unstructured":"Zhou L, Pei X, Zhang Y, Ning Y, Li L, Hu X, et al. Chk1 Inhibition potently blocks STAT3 tyrosine705 phosphorylation, DNA-binding activity, and activation of downstream targets in human multiple myeloma cells. Mol Cancer Res. 2022;20:456\u201367.","journal-title":"Mol Cancer Res"},{"key":"3607_CR42","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1158\/2326-6066.CIR-18-0071","volume":"7","author":"L Ding","year":"2019","unstructured":"Ding L, Chen X, Xu X, Qian Y, Liang G, Yao F, et al. PARP1 suppresses the transcription of PD-L1 by poly(ADP-Ribosyl)ating STAT3. Cancer Immunol Res. 2019;7:136\u201349.","journal-title":"Cancer Immunol Res"},{"key":"3607_CR43","doi-asserted-by":"publisher","first-page":"e005627","DOI":"10.1136\/jitc-2022-005627","volume":"11","author":"L Ding","year":"2023","unstructured":"Ding L, Wang Q, Martincuks A, Kearns MJ, Jiang T, Lin Z, et al. STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP Inhibition in ovarian cancer. J Immunother Cancer. 2023;11:e005627.","journal-title":"J Immunother Cancer"},{"key":"3607_CR44","doi-asserted-by":"publisher","first-page":"837","DOI":"10.7150\/jca.35011","volume":"11","author":"R Liang","year":"2020","unstructured":"Liang R, Chen X, Chen L, Wan F, Chen K, Sun Y, et al. STAT3 signaling in ovarian cancer: a potential therapeutic target. J Cancer. 2020;11:837\u201348.","journal-title":"J Cancer"},{"key":"3607_CR45","doi-asserted-by":"publisher","first-page":"724104","DOI":"10.3389\/fonc.2021.724104","volume":"11","author":"A Martincuks","year":"2021","unstructured":"Martincuks A, Song J, Kohut A, Zhang C, Li YJ, Zhao Q, et al. PARP Inhibition activates STAT3 in both tumor and immune cells underlying therapy resistance and immunosuppression in ovarian cancer. Front Oncol. 2021;11:724104.","journal-title":"Front Oncol"},{"key":"3607_CR46","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1111\/j.1365-2613.2010.00734.x","volume":"91","author":"SP Barry","year":"2010","unstructured":"Barry SP, Townsend PA, Knight RA, Scarabelli TM, Latchman DS, Stephanou A. STAT3 modulates the DNA damage response pathway. Int J Exp Pathol. 2010;91:506\u201314.","journal-title":"Int J Exp Pathol"},{"key":"3607_CR47","first-page":"1455","volume":"44","author":"Y Xu","year":"2020","unstructured":"Xu Y, Lin Y, Luo Y, Yang Y, Long B, Fang Z, et al. RAD52 aptamer regulates DNA damage repair and STAT3 in BRCA1\/BRCA2\u2013deficient human acute myeloid leukemia. Oncol Rep. 2020;44:1455\u201366.","journal-title":"Oncol Rep"},{"key":"3607_CR48","doi-asserted-by":"publisher","first-page":"3933","DOI":"10.3390\/ijms24043933","volume":"24","author":"R Gonnella","year":"2023","unstructured":"Gonnella R, Arena A, Zarrella R, Gilardini Montani MS, Santarelli R, Cirone M. HSPs\/STAT3 interplay sustains DDR and promotes cytokine release by primary effusion lymphoma cells. Int J Mol Sci. 2023;24:3933.","journal-title":"Int J Mol Sci"},{"key":"3607_CR49","doi-asserted-by":"publisher","first-page":"9715","DOI":"10.3390\/ijms21249715","volume":"21","author":"P Gralewska","year":"2020","unstructured":"Gralewska P, Gajek A, Marczak A, Miku\u0142a M, Ostrowski J, \u015aliwi\u0144ska A, et al. PARP Inhibition increases the reliance on ATR\/CHK1 checkpoint signaling leading to synthetic lethality-an alternative treatment strategy for epithelial ovarian cancer cells independent from HR effectiveness. Int J Mol Sci. 2020;21:9715.","journal-title":"Int J Mol Sci"},{"key":"3607_CR50","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.3390\/cells11121889","volume":"11","author":"P Gralewska","year":"2022","unstructured":"Gralewska P, Gajek A, Rybaczek D, Marczak A, Rogalska A. The influence of PARP, ATR, CHK1 inhibitors on premature mitotic entry and genomic instability in high-grade serous BRCAMUT and BRCAWT ovarian cancer cells. Cells. 2022;11:1889.","journal-title":"Cells"},{"key":"3607_CR51","doi-asserted-by":"publisher","first-page":"3726","DOI":"10.1038\/s41467-020-17127-2","volume":"11","author":"H Kim","year":"2020","unstructured":"Kim H, Xu H, George E, Hallberg D, Kumar S, Jagannathan V, et al. Combining PARP with ATR Inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun. 2020;11:3726.","journal-title":"Nat Commun"},{"key":"3607_CR52","first-page":"665","volume":"10","author":"CA Kholdani","year":"2014","unstructured":"Kholdani CA, Fares WH, Trow TK. Macitentan for the treatment of pulmonary arterial hypertension. Vasc Health Risk Manag. 2014;10:665\u201373.","journal-title":"Vasc Health Risk Manag"},{"key":"3607_CR53","doi-asserted-by":"publisher","first-page":"175346661882344","DOI":"10.1177\/1753466618823440","volume":"13","author":"C Belge","year":"2019","unstructured":"Belge C, Delcroix M. Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience. Ther Adv Respir Dis. 2019;13:1753466618823440.","journal-title":"Ther Adv Respir Dis"},{"key":"3607_CR54","doi-asserted-by":"publisher","first-page":"71","DOI":"10.2147\/DHPS.S173050","volume":"11","author":"AK Wong","year":"2019","unstructured":"Wong AK, Channick RN. Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update. Drug Healthc Patient Saf. 2019;11:71\u201385.","journal-title":"Drug Healthc Patient Saf"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03607-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-025-03607-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03607-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T15:05:50Z","timestamp":1781622350000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13046-025-03607-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,6]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3607"],"URL":"https:\/\/doi.org\/10.1186\/s13046-025-03607-0","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,6]]},"assertion":[{"value":"26 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ascitic fluids samples were obtained with the written consent of HG-SOC patients undergoing surgery for ovarian tumour at the Gynecological Oncology of IRCCS, Regina Elena National Cancer Institute of Rome. The study protocol for ascites collection and clinical information was approved by the Regina Elena Cancer Institute review board. All protocols involving human specimens are compliant with all relevant ethical regulations. Procedures involving animals and their care were conducted with the permission from the IRCCS Regina Elena Cancer Institute Animal Care and Use Committee and the Italian Ministry of Health (D.lgs 26\/2014, authorization number 1083\/2020PR, issued 5 November 2020 by Ministero della Salute).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors read and approved the final manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12"}}