Combined Inhibition Of G Alpha(Q) And Mek Enhances Therapeutic Efficacy In Uveal Melanoma

Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (G alpha(q)) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of G alpha(q) have shown promising preclinical results, but their therapeutic activity in distinct G alpha(q) mutational contexts and in vivo have remained elusive.Experimental Design: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in in vivo xenograft studies to assess the efficacy of G alpha(q) inhibition as a single agent and in combination with MEK inhibition.Results: We demonstrate that the G alpha(q) inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrated that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo.Conclusions: These data suggest that the combination of G alpha(q) and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting G alpha(q) in uveal melanoma.See related commentary by Neelature Sriramareddy and Smalley, p. 1217