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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Ovarian cancer (OCa) is a lethal malignancy, with KRAS mutations driving low-grade serous and mucinous subtypes.
• KRAS mutations activate MAPK and PI3K/AKT pathways, leading to tumor progression and treatment resistance.
• MEK inhibitor trametinib efficacy is limited by compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis in KRAS-mutant OCa.

Purpose of the Study:

• To evaluate the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor.
• To investigate the efficacy and mechanisms of action of this combination therapy in Ras/Raf-driven OCa models.

Main Methods:

• In vitro assessment of cell viability, clonogenic survival, and cell death (including ferroptosis) with EC359 treatment.
• Mechanistic studies to analyze LIFR downstream signaling suppression and RNA-sequencing (RNA-seq) for gene expression profiling.
• In vivo evaluation of tumor growth reduction in xenograft and patient-derived xenograft (PDX) models with EC359 and trametinib co-treatment.

Main Results:

• EC359 significantly reduced cell viability, clonogenic survival, and induced ferroptosis in vitro.
• Combination therapy suppressed LIFR signaling, downregulated mitochondrial translation and MYC target genes, and upregulated apoptosis-related genes.
• In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth without observed toxicity.

Conclusions:

• LIFR signaling represents a critical vulnerability in Ras/Raf-mutant and low-grade serous OCa.
• The combination of EC359 and trametinib offers a promising new therapeutic strategy for Ras/Raf-driven and low-grade serous OCa.
• This study provides a strong preclinical rationale for advancing this combination therapy.