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

TL;DR

Combining EC359 with trametinib improves treatment of Ras/Raf-driven ovarian cancer by blocking LIFR signaling and reducing tumor growth.

Contribution

The study introduces EC359 as a novel LIFR inhibitor that enhances trametinib's efficacy in Ras/Raf-driven ovarian cancer.

Findings

EC359 reduced cell viability and induced ferroptosis in Ras/Raf-driven ovarian cancer cells.

Combination therapy suppressed LIFR signaling and downregulated MYC and mitochondrial genes.

In vivo, the combination significantly reduced tumor growth without toxicity in xenograft and PDX models.

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.

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