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

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 (<i>LIF</i>)/<i>LIF</i> receptor (<i>LIFR</i>) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective <i>LIFR</i> inhibitor, in <i>Ras</i>/<i>Raf</i>-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 <i>LIFR</i> downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and <i>MYC</i> 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 <i>LIFR</i> signaling as a critical vulnerability in <i>Ras</i>/<i>Raf</i>-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 <i>Ras</i>/<i>Raf</i>-driven OCa and low-grade serous OCa.