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Ref Type Journal Article
PMID (33229459)
Authors Hitchman TD, Bayshtok G, Ceraudo E, Moore AR, Lee C, Jia R, Wang N, Pachai MR, Shoushtari AN, Francis JH, Guan Y, Chen J, Chang MT, Taylor BS, Sakmar TP, Huber T, Chi P, Chen Y
Title Combined Inhibition of Gα q and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 27 5 2021 Mar 01 1476-1490 Clin Cancer Res
URL
Abstract Text 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 in vivo have remained elusive. 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 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 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 . 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. See related commentary by Neelature Sriramareddy and Smalley, p. 1217 .

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