RASurgence：ARF6促进RAS癌蛋白合成并加速肿瘤进展。

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 (PIP 2 ), 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 NRAS Q61R 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.