Presentation: 2025 ND EPSCoR Annual conference 

October 21, 2025, NDSU Memorial Union, Fargo, North Dakota

RAGE inhibition sensitizes BRAF mutant melanoma cells to vemurafenib

BRAF mutations are present in over half of melanoma tumors, making vemurafenib a targeted treatment option for these patients. However, resistance to vemurafenib often develops within seven months after the treatment. The receptor for advanced glycation (RAGE) plays a critical role in melanoma progression by promoting cell proliferation and tumor cell survival through modulation of different signaling pathways regulated by PI3K/AKT. Moreover, RAGE has been implicated in therapy resistance through the regulation of autophagy. We hypothesize that RAGE inhibition enhances the sensitivity of melanoma cells to vemurafenib by decreasing cell proliferation, autophagy, and the signaling pathway regulated by PI3K/AKT. We investigated the synergistic effects of vemurafenib in combination with the RAGE inhibitor FPS.ZM1 in the WM115 human melanoma cell line. Cell viability was assessed using Alamar Blue, and drug synergy was analyzed using the Combenefit software. Changes in the levels of the signaling pathway regulator Akt were investigated by Western blot analysis, and the levels of the autophagic markers p62 and LC3-I/-II are currently being evaluated by the same method. Our initial data show increased activation of Akt in vemurafenib-treated cells, and the drug combination (Vemurafenib and FPS-ZM1) significantly reduces this activation. On the other hand, RAGE inhibition significantly increased the expression of adaptor protein p62, suggesting a reduction of the autophagic flux. Overall, our initial data suggest that RAGE inhibition sensitizes melanoma cells to vemurafenib by decreasing activation of the Akt signaling pathway and reducing autophagy.