Combined Inhibition of Gaq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma

We developed an isogenic melanocytic cellular system and systematically examined the hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (e.g. L129Q) in human uveal melanoma. Biochemical and cell viability assays validated YM-254890 as a potent inhibitor of cell signaling and growth. Human uveal melanoma cells and mouse models recapitulated this finding, indicating that YM is also effective in vivo. Combination of YM and MEK inhibition leads to further decreases in MAPK pathway gene expression and cell viability. Furthermore, our cellular and mouse models show that combination leads to long term signaling inhibition and significant decreases in tumor burden. Transcriptome analysis of melan-a cells (mouse) and two variant lines all in duplicate. Parental melan-a cells were compared to melan-a cells overexpressing GNAQ Q209L or KRAS G12V.