2. Academic Validation
  3. EC359 Enhances Trametinib Efficacy in Ras/ Raf-Driven Ovarian Cancer by Suppressing LIFR Signaling

EC359 Enhances Trametinib Efficacy in Ras/ Raf-Driven Ovarian Cancer by Suppressing LIFR Signaling

  • Biomolecules. 2025 Sep 30;15(10):1396. doi: 10.3390/biom15101396.
William C Arnold 1,  Durga Meenakshi Panneerdoss 1,  Baskaran Subramani 1,  Megharani Mahajan 1,  Behnam Ebrahimi 1,  Paulina Ramirez 1,  Bindu Santhamma 2,  Suryavathi Viswanadhapalli 1 3,  Edward R Kost 1,  Yidong Chen 4 5,  Zhao Lai 4 6,  Hareesh B Nair 7,  Ratna K Vadlamudi 1 3 8,  Yasmin A Lyons 1 3
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
  • 2 Evestra, Inc., San Antonio, TX 78245, USA.
  • 3 Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
  • 4 Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
  • 5 Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
  • 6 Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
  • 7 Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
  • 8 Audie L. Murphy Memorial Veterans Hospital, 7400 Merton Minter Boulevard, San Antonio, TX 78229, USA.
PMID: 41154625 DOI: 10.3390/biom15101396
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.

Keywords

EC359; LIFR; MAPK; Ras/Raf mutations; STAT3; low grade serous ovarian cancer; ovarian cancer; trametinib.

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