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HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

ABSTRACT: Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used unbiased multi-omics and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127948 | GEO | 2019/06/11

REPOSITORIES: GEO

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HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.

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HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

Project description:HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

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Combined Inhibition of Gaq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma

Project description:We developed an isogenic melanocytic cellular system and systematically examined the hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (e.g. L129Q) in human uveal melanoma. Biochemical and cell viability assays validated YM-254890 as a potent inhibitor of cell signaling and growth. Human uveal melanoma cells and mouse models recapitulated this finding, indicating that YM is also effective in vivo. Combination of YM and MEK inhibition leads to further decreases in MAPK pathway gene expression and cell viability. Furthermore, our cellular and mouse models show that combination leads to long term signaling inhibition and significant decreases in tumor burden.

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

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The HDAC inhibitor panobinostat (LBH589) inhibits Acute Lymphoblastic leukemia (ALL) in vitro and in vivo in a new characterized human ALL mice model

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HDAC inhibition suppresses telomerase activity in neuroblastoma cells harboring TERT rearrangements [array]

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Combined Inhibition of Gaq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma

Project description:Combined Inhibition of Gaq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma

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

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RNA-seq analysis of MEK or ERK1/2 inhibitor treatment in uveal melanoma cell lines.

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