Abstract 5989: Investigating the potential of EC359 in inducing ferroptosis for the treatment of type I and type II endometrial cancers

Abstract Background: Over the past decade, the diagnostic and mortality rates of endometrial cancer, the most common malignancy of the female reproductive tract, have risen, highlighting the need for improvements in current therapeutic options. Recent studies suggest that targeting the cellular receptor LIFR with the small molecule inhibitor EC359 could be a potential treatment for endometrial cancers. EC359 has been shown to inhibit the viability and invasion of both Type I and Type II endometrial cancers. However, the underlying mechanisms by which EC359 induces cancer cell death remain unclear. Emerging evidence suggests that LIFR signaling may be linked to ferroptosis. The purpose of this study is to explore the potential of EC359 to induce ferroptosis as a therapeutic strategy for Type I and Type II endometrial cancers. Methods: The effects of EC359 on multiple established and primary endometrial cancer cells were evaluated using colony formation, MTT based cell viability and apoptosis assays. Mechanistic investigations were performed with Western blot, RT-qPCR, transmission electron microscopy (TEM) evaluation, and Flow Cytometry analysis. Patient-derived xenograft (PDX) models were used for preclinical evaluation of EC359. Results: EC359 was efficient in reducing cell viability and promoting programmed cell death in both Type I and Type II endometrial cancer cells. We have demonstrated that the ability of EC359 to reduce cell viability is markedly diminished when ferroptosis is inhibited by pharmacological agents like Ferrostatin 1. EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system, as demonstrated by mechanistic investigations using Western blot analysis. Accordingly, the viability of endometrial cancer cells is restored by the addition of extracellular cystine. Further, EC359 treatment resulted in the reduction of critical anti-ferroptosis proteins. Flow cytometry analyses confirmed that EC359 treatment resulted in an increase in lipid peroxidation and TEM investigations revealed the induction of mitochondrial death through ferroptosis. Additionally, EC359 substantially inhibited the progression of tumors in both Type I and II endometrial cancer PDX models. Conclusion: In conclusion, our data indicate that EC359 is a potent inducer of ferroptosis in endometrial cancer cells and has the potential to be used as an additional tool in current endometrial cancer treatment regimens. Citation Format: Emily J. Aller, Xue Yang, Megharani R. Mahajan, Behnam Ebrahimi, Paulina Ramirez, Hareesh B. Nair, Edward Kost, Ratna K. Vadlamudi, Suryavathi Viswanadhapalli. Investigating the potential of EC359 in inducing ferroptosis for the treatment of type I and type II endometrial cancers [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 5989.