{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T16:01:09Z","timestamp":1759334469716,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MCC Pilot grant","award":["NIH R01 CA267893","NIH R01 CA266970-01A1","VA I01 BX006280-01","NCI F99 CA284284-01","NIH NCI R50 CA265339"],"award-info":[{"award-number":["NIH R01 CA267893","NIH R01 CA266970-01A1","VA I01 BX006280-01","NCI F99 CA284284-01","NIH NCI R50 CA265339"]}]},{"name":"AstraZeneca Young Investigator award"},{"name":"Cancer Center at UT Health San Antonio","award":["NIH-NCI P30 CA054174"],"award-info":[{"award-number":["NIH-NCI P30 CA054174"]}]},{"name":"NIH Shared Instrumentation","award":["1S10 OD030311-01"],"award-info":[{"award-number":["1S10 OD030311-01"]}]},{"name":"the CPRIT Core Facility Award","award":["RP220662"],"award-info":[{"award-number":["RP220662"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mutations. These mutations activate downstream MAPK and PI3K\/AKT signaling pathways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)\/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras\/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in xenograft and PDX models without inducing toxicity. Our studies identify LIFR signaling as a critical vulnerability in Ras\/Raf-mutant and low grade serous OCa. Further, it provides strong preclinical rationale for EC359 and trametinib combination therapy as a new therapeutic strategy for treating Ras\/Raf-driven OCa and low-grade serous OCa.<\/jats:p>","DOI":"10.3390\/biom15101396","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T16:43:54Z","timestamp":1759250634000},"page":"1396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["EC359 Enhances Trametinib Efficacy in Ras\/Raf-Driven Ovarian Cancer by Suppressing LIFR Signaling"],"prefix":"10.3390","volume":"15","author":[{"given":"William C.","family":"Arnold","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Durga Meenakshi","family":"Panneerdoss","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6966-3484","authenticated-orcid":false,"given":"Baskaran","family":"Subramani","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megharani","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Behnam","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bindu","family":"Santhamma","sequence":"additional","affiliation":[{"name":"Evestra, Inc., San Antonio, TX 78245, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7381-6962","authenticated-orcid":false,"given":"Suryavathi","family":"Viswanadhapalli","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward R.","family":"Kost","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yidong","family":"Chen","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao","family":"Lai","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0364-7518","authenticated-orcid":false,"given":"Hareesh B.","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2849-4076","authenticated-orcid":false,"given":"Ratna K.","family":"Vadlamudi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Audie L. Murphy Memorial Veterans Hospital, 7400 Merton Minter Boulevard, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmin A.","family":"Lyons","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA"},{"name":"Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/nrc4019","article-title":"Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer","volume":"15","author":"Bowtell","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1002\/cncr.32004","article-title":"Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference","volume":"125","author":"Bast","year":"2019","journal-title":"Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s00428-012-1203-5","article-title":"Ovarian carcinomas: Five distinct diseases with different origins, genetic alterations, and clinicopathological features","volume":"460","author":"Prat","year":"2012","journal-title":"Virchows Arch."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e70089","DOI":"10.1096\/fj.202401734R","article-title":"Targeting KRAS in gynecological malignancies","volume":"38","author":"Peng","year":"2024","journal-title":"FASEB J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1038\/sj.bjc.6604783","article-title":"KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer","volume":"99","author":"Nakayama","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/S0140-6736(21)02175-9","article-title":"Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281\/LOGS): An international, randomised, open-label, multicentre, phase 2\/3 trial","volume":"399","author":"Gershenson","year":"2022","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.cytogfr.2015.07.001","article-title":"Leukemia inhibitory factor (LIF)","volume":"26","author":"Nicola","year":"2015","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1126\/science.8272873","article-title":"Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components","volume":"263","author":"Stahl","year":"1994","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"788","DOI":"10.18632\/oncotarget.1772","article-title":"LIF promotes tumorigenesis and metastasis of breast cancer through the AKT-mTOR pathway","volume":"5","author":"Li","year":"2014","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5269","DOI":"10.1172\/JCI63428","article-title":"Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance","volume":"123","author":"Liu","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41586-019-1130-6","article-title":"Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring","volume":"569","author":"Shi","year":"2019","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.1038\/s41467-019-11044-9","article-title":"Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer","volume":"10","author":"Wang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1158\/1535-7163.MCT-18-1258","article-title":"EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer","volume":"18","author":"Viswanadhapalli","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/s41420-021-00603-z","article-title":"LIF\/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer","volume":"7","author":"Tang","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Blankenship, L., Pratap, U.P., Yang, X., Liu, Z., Altwegg, K.A., Santhamma, B., Ramasamy, K., Konda, S., Chen, Y., and Lai, Z. (2022). Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth. Cancers, 14.","DOI":"10.3390\/cancers14215400"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18632\/genesandcancer.184","article-title":"Utilizing cell line-derived organoids to evaluate the efficacy of a novel LIFR-inhibitor, EC359 in targeting pancreatic tumor stroma","volume":"10","author":"Hall","year":"2019","journal-title":"Genes. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Di Giorgio, C., Lupia, A., Marchiano, S., Bordoni, M., Bellini, R., Massa, C., Urbani, G., Roselli, R., Moraca, F., and Sepe, V. (2022). Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma. Cells, 11.","DOI":"10.3390\/cells11213482"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.gendis.2022.10.016","article-title":"The LIFR-targeting small molecules EC330\/EC359 are potent ferroptosis inducers","volume":"10","author":"Feng","year":"2023","journal-title":"Genes Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41698-024-00612-y","article-title":"Pharmacological inhibition of the LIF\/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis","volume":"8","author":"Ebrahimi","year":"2024","journal-title":"NPJ Precis. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1593\/neo.121712","article-title":"Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor\/HER2 inhibitor lapatinib","volume":"15","author":"Walters","year":"2013","journal-title":"Neoplasia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"i16","DOI":"10.1093\/annonc\/mdw089","article-title":"The molecular pathology of ovarian serous borderline tumors","volume":"27","author":"Malpica","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sasaki, N., Hirano, K., Shichi, Y., Gomi, F., Yoshimura, H., Matsushita, A., Toyoda, M., and Ishiwata, T. (2022). Gp130-Mediated STAT3 Activation Contributes to the Aggressiveness of Pancreatic Cancer through H19 Long Non-Coding RNA Expression. Cancers, 14.","DOI":"10.3390\/cancers14092055"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jorgensen, M.M., and de la Puente, P. (2022). Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer. Biomolecules, 12.","DOI":"10.3390\/biom12020217"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107754","DOI":"10.1016\/j.pharmthera.2020.107754","article-title":"The emerging role of leukemia inhibitory factor in cancer and therapy","volume":"221","author":"Zhang","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102137","DOI":"10.1016\/j.ctrv.2020.102137","article-title":"MEK inhibitor resistance mechanisms and recent developments in combination trials","volume":"92","author":"Kun","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7095","DOI":"10.2147\/OTT.S182721","article-title":"Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma","volume":"11","author":"Kakadia","year":"2018","journal-title":"OncoTargets Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s40265-018-0884-8","article-title":"BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers","volume":"78","author":"Sanchez","year":"2018","journal-title":"Drugs"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1396\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T16:47:43Z","timestamp":1759250863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1396"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":28,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["biom15101396"],"URL":"https:\/\/doi.org\/10.3390\/biom15101396","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2025,9,30]]}}}