{"doi":"10.3390/biom15101396","title":"EC359 Enhances Trametinib Efficacy in Ras/Raf-Driven Ovarian Cancer by Suppressing LIFR Signaling","abstract":"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.","journal":"Biomolecules","year":2025,"id":576402,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE306834"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1485309,"name":"Durga Meenakshi Panneerdoss","orcid":null,"position":1,"is_corresponding":false},{"id":1484878,"name":"Baskaran Subramani","orcid":"0000-0001-6966-3484","position":2,"is_corresponding":false},{"id":1259229,"name":"Megharani Mahajan","orcid":"0000-0002-6259-5754","position":3,"is_corresponding":false},{"id":715021,"name":"Behnam Ebrahimi","orcid":"0000-0003-4588-7525","position":4,"is_corresponding":false},{"id":1002539,"name":"Paulina Ramirez","orcid":null,"position":5,"is_corresponding":false},{"id":405154,"name":"Bindu Santhamma","orcid":"0000-0002-5569-2185","position":6,"is_corresponding":false},{"id":354371,"name":"Suryavathi Viswanadhapalli","orcid":"0000-0002-7381-6962","position":7,"is_corresponding":false},{"id":506825,"name":"Edward R. Kost","orcid":"0000-0001-9613-1643","position":8,"is_corresponding":false},{"id":389888,"name":"Yidong Chen","orcid":"0000-0002-3154-6511","position":9,"is_corresponding":false},{"id":263243,"name":"Zhao Lai","orcid":"0000-0002-3543-5376","position":10,"is_corresponding":false},{"id":634475,"name":"Hareesh B. Nair","orcid":"0000-0002-0364-7518","position":11,"is_corresponding":false},{"id":275898,"name":"Ratna K. Vadlamudi","orcid":"0000-0003-2849-4076","position":12,"is_corresponding":false},{"id":691023,"name":"Yasmin A. Lyons","orcid":"0000-0002-2558-3201","position":13,"is_corresponding":false},{"id":1259644,"name":"William C. Arnold","orcid":null,"position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T02:57:56.636458Z","pmid":"41154625","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}