Abstract B051: Targeting RAS to stimulate pyroptosis and antitumor immunity in acral melanoma

Abstract Acral melanoma is a rare and understudied subtype of melanoma that arises on the palms, soles, and nailbeds. The standard of care for advanced stage disease is immune checkpoint blockade, but patient responses are poor due to the suppressive tumor immune microenvironment. RAS is a promising target for acral melanoma as tumors frequently have increased RAS GTPase activity through genetic alterations in RAS and genes regulating RAS. To understand the therapeutic potential of targeting RAS, we assessed the activity of RMC-7977, a novel RAS (ON) multi-selective inhibitor that targets the active GTP-bound state of both wildtype and mutant RAS isoforms, in acral melanoma cells. RMC-7977 inhibited growth and caused cell death via pyroptosis in NRAS-mutant cell lines. Pyroptosis is a form of immunogenic cell death that is mediated by gasdermin proteins and can elicit an antitumor immune response. Our preliminary data suggest that pyroptosis is mediated by gasdermin E cleavage and activation. Cytokine arrays showed that RMC-7977 alters the release of cytokines and inflammatory molecules from acral melanoma cells, including decreased IL-10 and IL-6 release and increased MIF and TNFRI release. Additionally, RNA-sequencing data of RAS-mutant acral melanoma cells treated with RMC-7977 suggest downregulation of immune checkpoint proteins including PD-L1, B7-H3, and CD155, suggesting modulation of the tumor immune microenvironment. Future studies will determine the mechanistic requirements for GSDME through add-back experiments into GSDME knockout cells. We will understand how secreted cytokines regulate pyroptosis and the tumor immune microenvironment in the context of RMC-7977 treatment. We will further investigate how RMC-7977 alters the immune microenvironment by characterizing changes in tumor cell surface proteins and examining effects on immune cell infiltration using human acral melanoma tumor organoid-immune co-culture models. RMC-7977, as a pyroptosis-inducing agent, may be an effective treatment strategy in RAS-activated acral melanomas to inflame the cold tumor immune microenvironment and bolster antitumor immune responses. Citation Format: Geethanjali Annamalai, Glenn L. Mersky, Charlie Barraclough, Patricia A. Possik, Andrew E. Aplin. Targeting RAS to stimulate pyroptosis and antitumor immunity in acral melanoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr B051.