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|Ref Type||Journal Article|
|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|
|Date||2020 Nov 23|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|
|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|
|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|
|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|