Abstract LB217: RAGE inhibition improves vemurafenib effect in melanoma cells

Abstract Background: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that participates to many aspects of tumorigenesis including cancer cell proliferation, migration, invasion. RAGE also contributes to resistance to chemotherapeutic agents. We have previously shown that RAGE inhibition, with the small molecule RAGE inhibitor (FPS-ZM1), increased the efficacy of the chemotherapeutic agent dacarbazine, in a mouse model of melanoma. We later showed that RAGE inhibition also enhances the efficacy of the cytotoxic agent gemcitabine in an orthotopic mouse model of pancreatic cancer, suggesting that RAGE inhibition could enhance the efficacy of different chemotherapeutic agents in different types of cancer. Objective of the study: The goal of our study was to determine if RAGE inhibition increases the efficacy of the BRAF V600E mutant inhibitor vemurafenib in melanoma cells.Methodology:We assessed the synergistic or antagonistic effect of the small molecule RAGE inhibitor, FPS-ZM1, combined with the current standard of care vemurafenib. We compared the viability of human melanoma WM115 cells after treatment with different concentrations of vemurafenib and FPS-ZM1. The data were analyzed for the presence of synergistic effect using a dedicated software. Results and conclusion: As anticipated, treatment of WM115 cells with FPS-ZM1 alone did not affect the viability of the melanoma cells. However, when combined with vemurafenib, FPS-ZM1 enhanced the apparent IC50 of vemurafenib by 2 to 3-fold, suggesting that RAGE inhibition enhances the efficacy of vemurafenib in WM115 cells and possibly in other melanoma cells. We will next investigate if RAGE inhibition also enhances the efficacy of vemurafenib in a mouse model of melanoma. Citation Format: Estelle Leclerc, Yousuf Alam, Md. Zahidul Hasan, Stefan W. Vetter. RAGE inhibition improves vemurafenib effect in melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB217.