Abstract 5985: Low-grade serous ovarian cancer is effectively treated with a combination of trametinib and LIFR inhibitor therapeutics

Abstract Background: Ovarian cancer (OCa) is the most lethal gynecologic malignancy in the United States, with low-grade serous ovarian carcinoma (LGSOC) constituting 10% of cases. LGSOC is characterized by slow progression, resistance to treatment, and mutations in BRAF (33%) and KRAS (35%). LGSOC is often diagnosed at an advanced stage with a 70% relapse rate. Thus, novel targeted therapies are needed. Trametinib, a kinase inhibitor, is used to treat KRAS-mutated cancers, but our studies show that it increases LIFR expression, forming an autocrine LIF/LIFR oncogenic signaling loop that reduces Trametinib effectiveness in LGSOC treatment. This study tests the hypothesis that targeting the LIF/LIFR axis can enhance trametinib's efficacy in treating LGSOC. Methods: The combination effects of EC359 and Trametinib on LGSOC cells were evaluated using cell viability, colony formation, invasion, and apoptosis assays. Mechanistic studies were performed using Western blotting, RT-qPCR and RNA-seq. The in vivo efficacy of trametinib and LIFR inhibitor EC359 as a targeted combination therapy was tested using LGSOC cell-based xenografts. Immunohistochemistry was conducted on the xenograft tumor sections to assess the proliferative index through Ki67 antibody staining. Results: Trametinib increased the expression of LIFR in LGSOC cells in a time-dependent manner, as confirmed by Western blotting analyses, but not in HGSOC cells. In multiple LGSOC cell models, the combination therapy of EC359 and trametinib exhibited superior efficacy in reducing cell viability, colony formation, as well as increasing apoptosis, when compared to monotherapies with either EC359 or trametinib. The biochemical analyses of these models demonstrated that trametinib treatment activated the LIFR signaling pathway, which included the activation of LIFR downstream effectors such as STAT3, mTOR, and AKT. However, this activation was significantly reduced when combined with EC359. In addition, the growth of LGSOC xenograft tumors was substantially suppressed by treatment with EC359 at a dose of 5mg/kg in cell-based xenograft models in comparison to the vehicle control. Furthermore, the tumor-suppressive effects of trametinib were further enhanced by EC359, which resulted in a further reduction in tumor growth. The proliferative marker Ki67 was significantly reduced in tumors treated with the combination therapy, as evidenced by immunohistochemical analysis, suggesting a potent anti-proliferative effect. Conclusions: These results indicate that the EC359 + trametinib combination therapy may provide a promising therapeutic approach for the treatment of LGSOC by enhancing the efficacy of trametinib and targeting critical signaling pathways. Citation Format: William C. Arnold, Durga Meenakshi Panneerdoss, Suryavathi Viswanadhapalli, Behnam Ebrahimi, Hareesh B. Nair, Ratna K. Vadlamudi, Yasmin A. Lyons. Low-grade serous ovarian cancer is effectively treated with a combination of trametinib and LIFR inhibitor therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5985.