Abstract 5979: RASurgence: ARF6 boosts RAS oncoprotein synthesis and accelerates tumor progression

Abstract Oncogenic mutations in RAS genes occur in approximately twenty percent of all cancers and drive lethal malignancies such as lung, pancreatic, colorectal carcinoma and melanoma. Despite decades of research, RAS-mutant cancers remain difficult to treat and resistance to emerging RAS targeted therapies is a major clinical challenge. The small GTPase ADP-Ribosylation Factor 6 (ARF6), a member of the RAS superfamily, is critical for endomembrane trafficking, cytoskeletal remodeling, and production of phosphatidylinositol 4,5-bisphosphate (PIP2), a substrate for PI3K and PLC lipid signaling. We have previously shown that ARF6 mediates invasion, metastasis and adaptive immune suppression in BRAF-mutant melanoma. Here we present preliminary data suggesting that ARF6 supports survival of RAS-mutant cancer cells and accelerates RAS-driven tumor progression by augmenting oncoprotein expression. In human NRAS-mutant melanoma and KRAS-mutant carcinoma cells, inhibition or knockdown of ARF6 significantly reduces viability. In genetically engineered, immunocompetent mice bearing NRASQ61R melanomas, tumor-specific deletion of Arf6 delays tumor onset, slows tumor growth and prolongs overall survival. Mechanistically, activation of ARF6 stimulates PI3K-AKT-mTOR signaling and increases expression of RAS, BRAF and PI3K oncoproteins, at least partly through mTOR-mediated protein translation. Together these data suggest that oncogenic RAS signaling relies on ARF6 to fortify expression of key oncoproteins in the RAS pathway and enhance tumor progression. Citation Format: Gwen Kramer, Deja M. Brooks, Joshua Tay, Prachi Gupta, Sheri L. Holmen, Thomas Jacob, Allie H. Grossmann. RASurgence: ARF6 boosts RAS oncoprotein synthesis and accelerates tumor progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5979.