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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 Gαq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol
Issue
Date 2020 Nov 23
URL
Abstract Text All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gαq) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gαq have shown promising preclinical results, but their therapeutic activity in distinct Gαq 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 Gαq inhibition as a single agent and in combination with MEK inhibition.We demonstrate that the Gαq 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 Gαq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gαq in uveal melanoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
YM-254890 YM254890|YM 254890 YM-254890 is a specific inhibitor of the G protein-coupled receptor, Gq (PMID: 31539242), that inhibits the exchange reaction of GDP/GTP by inhibiting the release of GDP (PMID: 20639466), and may lead to inhibition of cell proliferation and tumor formation (PMID: 33229459).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61K uveal melanoma no benefit YM-254890 Preclinical - Cell culture Actionable In a preclinical study, transformed mouse melanocytes expressing NRAS Q61K were insensitive to treatment with YM-254890 (PMID: 33229459). 33229459
BRAF V600E uveal melanoma no benefit YM-254890 Preclinical - Cell culture Actionable In a preclinical study, transformed mouse melanocytes expressing BRAF V600E were insensitive to treatment with YM-254890 (PMID: 33229459). 33229459
BRAF V600E skin melanoma no benefit YM-254890 Preclinical - Cell culture Actionable In a preclinical study, YM-254890 treatment did not inhibit cell viability of a cutaneous melanoma cell line harboring BRAF V300E in culture (PMID: 33229459). 33229459
BRAF V600E skin melanoma no benefit Trametinib + YM-254890 Preclinical - Cell culture Actionable In a preclinical study, combination treatment with YM-254890 and Mekinist (trametinib) did not result in synergistic inhibition of cell viability of a cutaneous melanoma cell line harboring BRAF V600E in culture (PMID: 33229459). 33229459