Combined Inhibition of Gα_q and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.

Abstract

All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gα_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 Gα_q have shown promising preclinical results, but their therapeutic activity in distinct Gα_q mutational contexts and <i>in vivo</i> have remained elusive. We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in <i>GNAQ</i> (e.g., G48V, R183Q, Q209L) and <i>CYSLTR2</i> (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used <i>in vitro</i> and in <i>in vivo</i> xenograft studies to assess the efficacy of Gα_q inhibition as a single agent and in combination with MEK inhibition. We demonstrate that the Gα_q inhibitor YM-254890 inhibited downstream signaling and <i>in vitro</i> growth in all mutants. <i>In vivo</i>, 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 <i>in vitro</i> and tumor shrinkage <i>in vivo</i>. These data suggest that the combination of Gα_q and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gα_q in uveal melanoma.<i>See related commentary by Neelature Sriramareddy and Smalley, p. 1217</i>.