Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ACCESS DATA

Json Xml

Similar Datasets

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.

2020-05-26 | PXD013988 | Pride

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

| PRJNA525852 | ENA

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.

2020-12-31 | GSE152705 | GEO

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

2020-12-31 | GSE160112 | GEO

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

Project description:This SuperSeries is composed of the following subset Series: GSE26789: The HDAC inhibitor panobinostat (LBH589) inhibits Acute Lymphoblastic leukemia (ALL) in vitro and in vivo in a new characterized human ALL mice model (ALL-B and ALL-T) GSE26790: The HDAC inhibitor panobinostat (LBH589) inhibits Acute Lymphoblastic leukemia (ALL) in vitro and in vivo in a new characterized human ALL mice model (TOM-1 and MOLT-4) GSE26791: The HDAC inhibitor panobinostat (LBH589) inhibits Acute Lymphoblastic leukemia (ALL) in vitro and in vivo in a new characterized human ALL mice model (Illumina) GSE26792: The HDAC inhibitor panobinostat (LBH589) inhibits Acute Lymphoblastic leukemia (ALL) in vitro and in vivo in a new characterized human ALL mice model (SNP) Refer to individual Series

2012-04-17 | E-GEOD-26807 | biostudies-arrayexpress

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

Project description:Genome wide DNA methylation profiling of high-risk TERT-rearranged neuroblastoma cells treated with solvent or HDAC inhibitor panobinostat. The Illumina HumanMethylation EPIC Beadchip was used to obtain DNA methylation profiles. Samples included 3 solvent treated samples and 3 panobinostat-treated samples after 18 h of treatment.

2022-08-04 | GSE155703 | GEO

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.

| PRJNA640159 | ENA

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

| PRJNA671868 | ENA

Comprehensive evaluation of MEK inhibitors for malignant peripheral nerve sheath tumors reveals differences in efficacy and drug resistance development

Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas which lack effective drugs. Previous studies support the usefulness of MEK inhibitors (MEKis) for treating RAS-driven tumors, however, the lack of preclinical assessment of MEK inhibitors in MPNSTs limit the clinical application as well as the development of combination therapy. In this study, we comprehensively evaluated 8 MEK inhibitors in terms of efficiency, safety and mechanisms of resistance for treating MPNSTs. We identified the most promising MEK inhibitor, trametinib, for the treatment of MPNSTs. Through high-throughput transcriptomic sequencing and drug screening, we discovered the upregulation of integrin signaling contributing to MEK inhibitor resistance, termed as cell adhesion-mediated drug resistance (CAM-DR). We also confirmed MET overactivation in MEKi-resistant MPNST cells. These targets are potential solutions to overcome MEKi- resistance in clinical applications.

2022-07-26 | GSE174100 | GEO

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

Project description:Activating GNAQ/GNA11 are present in majority of uveal melanomas resulting in downstream activation of the MAPK pathway. To elucidate changes in the transcriptome after MEK or ERK1/2 inhibition, we performed RNA sequencing on two UM cell lines. Differential analysis revealed that MARK3 expression was not altered but STK10 expression was reduced.

2023-12-20 | GSE228090 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data