Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2020 Nov 23	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 (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
YM-254890	YM-254890	3	0

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 V600E 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