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Standard therapy includes platinum agents, but responses are poor. OCS highly express mesenchymal markers, such as N-MYC and HMGA2. The microtubule-targeting drug eribulin can reduce expression of N-MYC and HMGA2 in OCS PDX models and functionally reverse EMT in OCS cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we carried out drug screens in the presence of cisplatin or eribulin to identify synergistic combinations. We validated top combinations in our unique OCS cell line, organoid and PDX models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The most effective combination treatments in OCS organoid models involved eribulin, whereas cisplatin-based combination therapies were more effective in high-grade serous ovarian cancer (HGSOC) models. Eribulin combined with either an EGFR inhibitor (erlotinib) or a MEK inhibitor (mirdametinib\/PD0325901) were the most effective combinations in OCS models, with a synergistic effect being observed in two (out of four) models for each combination. Mechanistically, OCS models appeared to be particularly reliant on EGFR and MAPK signalling in vitro, especially in tumours with\n                      <jats:italic>TP53<\/jats:italic>\n                      mutation. In vivo, only modest improvements in survival were observed for eribulin plus erlotinib, however, two of the three OCS PDX models tested were found to have drug resistance mechanisms, such as high\n                      <jats:italic>ABCB1<\/jats:italic>\n                      expression (encoding the multi-drug resistance protein which causes drug efflux) or a KRAS constitutive activation mutation (a known resistance mechanism to EGFR inhibitors). KRAS mutant OCS cell lines and organoids were sensitive to dual targeting of the EGFR\/MAPK pathway, with statistically greater synergy observed when eribulin was added as a third drug.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>OCS is the most aggressive, drug-resistant gynaecological malignancy and eribulin-based combination therapies, particularly triple combination therapies, have the potential to improve patient outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03629-8","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T06:45:09Z","timestamp":1767681909000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High-throughput drug screening identifies EGFR\/MAPK pathway targeting sensitivities in organoid models of ovarian carcinosarcoma"],"prefix":"10.1186","volume":"45","author":[{"given":"Andrew","family":"Farrell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve","family":"Dall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra J.","family":"Vandenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Shield-Artin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L.","family":"Kyran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Blackmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratana","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Neagle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayanie","family":"Ratnayake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitri","family":"Mouradov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Hadla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Jarman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Beard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Jarratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn S.","family":"Penington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Wakefield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Papenfuss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare L.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly E.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"issue":"2","key":"3629_CR1","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1111\/j.1525-1438.2006.00760.x","volume":"17","author":"MS Mano","year":"2007","unstructured":"Mano MS, Rosa DD, Azambuja E, Ismael G, Braga S, D\u2019Hondt V, Piccart M, Awada A. 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Cancer Discov. 2021;11(1):92\u2013107.","journal-title":"Cancer Discov"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-025-03629-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03629-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03629-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T11:03:30Z","timestamp":1770203010000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13046-025-03629-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":93,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3629"],"URL":"https:\/\/doi.org\/10.1186\/s13046-025-03629-8","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]},"assertion":[{"value":"10 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Deidentified patient samples and corresponding clinical information were obtained from patients enrolled in the WEHI-Stafford Fox Rare Cancer Program (SFRCP); all patients provided informed written consent. Ethics approval for the WEHI-SFRCP was obtained from the Royal Melbourne Hospital Human Research Ethics Committee (Project number 2015.300) and governance review by the WEHI HREC (Project number G16\/02). All animal experiments were conducted according to the National Health and Medical Research Council Australian Code for the Care and Use of Animals for Scientific Purposes 8th Edition, 2013 (updated 2021), and under the approval of the WEHI Animal Ethics Committee (2019.024 and 2022.030).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have read and agreed to the published version of the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Eisai Inc provided drug support for this study. C.L.S. declares Advisory Boards for AstraZeneca, Clovis Oncology, Roche, Eisai Inc, Sierra Oncology, Takeda, MSD and Grant\/Research support from Eisai Inc, AstraZeneca, Boehringer Ingelheim and IDEAYA Biosciences. C.JV., R.L., C.N., M.J.W. and H.E.B. report research support (paid to institution) from AstraZeneca Pty Ltd and Boehringer Ingelheim outside the submitted work. Other authors declare no conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"32"}}