Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

EIF4A inhibition disrupts resistance-associated translational and metabolic programs in BRAF-mutant melanoma

ABSTRACT: Acquired resistance to BRAF inhibition is accompanied by broad gene-expression remodeling. We profiled parental A375 and acquired BRAF-inhibitor-resistant A375R melanoma cells using paired input and polysome-associated RNA sequencing and determined the acute response of A375R cells to the eIF4A inhibitor CR-1-31-B. An independent total-RNA-seq experiment measured later RNA-abundance responses after 24 h. These data distinguish resistance-associated RNA-abundance and translation-efficiency regulation and define early and later molecular responses to eIF4A inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE344859 | GEO | 2026/09/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Quantitative diaPASEF proteomics of A375 and A375R melanoma cells treated with CR-1-31-B

Project description:This dataset contains label-free data-independent acquisition proteomics from parental A375 human melanoma cells and the PLX4032-selected, BRAF-inhibitor-resistant derivative A375R. Four independent biological replicates per cell state were treated for 36 hours with matched DMSO or CR-1-31-B (10 nM), yielding 16 diaPASEF acquisitions. The experiment was designed to define proteomic programs associated with acquired BRAF-inhibitor resistance and their response to eIF4A inhibition.

2026-09-17 | PXD083257 | Pride

Analysis of A375 and A375 clones that acquired resistance to GSK2118436 after treatment with GSK2118436 (GSK436), GSK1120212 (GSK212), or the combination of GSK2118436 and GSK1120212 for 24 hour

Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al. A375 and 16R6-4 (an A375 derived GSK2118436 resistance clone) were treated for 24 hours with 0.1 micromolar GSK2118436, 1 micromolar GSK2118436, 0.01 micromolar GSK1120212, 0.1 micromolar GSK2118436 + 0.01 micromolar GSK1120212, or 1 micromolar GSK2118436 + 0.01 micromolar GSK1120212.

2012-02-01 | E-GEOD-35230 | biostudies-arrayexpress

Analysis of A375 and A375 clones that acquired resistance to GSK2118436 after treatment with GSK2118436 (GSK436), GSK1120212 (GSK212), or the combination of GSK2118436 and GSK1120212 for 24 hour

2012-02-01 | GSE35230 | GEO

RNA-seq melanoma

2014-01-04 | GSE50535 | GEO

RNA-seq melanoma

Project description:Using a chromatin regulator-focused shRNA library, we found that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes resistance to BRAF and MEK inhibitors. To investigate how SOX10 loss leads to drug resistance, we performed transcriptome sequencing (RNAseq) of both parental A375 (Ctrl. PLKO) and A375-SOX10KD (shSOX10-1, shSOX10-2) cells. To ask directly whether SOX10 is involved indrug resistance in BRAF(V600E) melanoma patients, we isolated RNA from paired biopsies from melanoma patients (pre- and post- treatment) , that had gained BRAF or MEK inhibitor resistance . We performed RNAseq analysis to determine changes in transcriptome upon drug resistance. Investigate genes regulated by SOX10 and differntial gene expression between pre- and post-treatment biopsies. We use short hairpin RNA to suppression SOX10 in A375 cells and cells were harvested with trizol reagent for RNA isolation. For paired biopsies (patient samples) we collected the first biopsy before the initiation of treatment and the second biopsy after drug resistance developed. RNA was isolated from FFPE samples and subjected for RNA sequencing.

2014-01-04 | E-GEOD-50535 | biostudies-arrayexpress

A four-arm study of A375 melanoma cell line-derived xenograft tumors in NSG mice treated with Vemurafenib and CB839

Project description:Melanoma is a rare but deadly form of skin cancer, which is often treated with BRAF inhibitors such as Vemurafenib (referred to as PLX4032). Whilst Vemurafenib prolongs the survival of patients, BRAF inhibitor resistance inevitably occurs in most cases. Previous studies demonstrated that metabolic rewiring occurs in BRAF inhibitor resistance and causes dependence on glutamine. To investigate whether this vulnerability could be exploited with clinically relevant drugs, we used the BRAF inhibitor, Vemurafenib, and the glutaminase imhibitor, CB839 to treat A375-derived melanoma xenografted tumors. We showed that whilst CB839 did not significantly affect the growth of A375-derived tumors compared to those given a vehicle, the addition of CB839 to Vemurafenib treatment had a significant anti-tumor effect. Tumors were taken at the endpoint (Max tumor length 15mm) from the 6 mice in each treatment group and cut into fragments and stored in RNAlater for RNAseq analysis. RNA extraction was performed on 1-3 fragments per tumor to make up 200-300mg of tissue.

2023-04-07 | E-MTAB-12811 | biostudies-arrayexpress

Ribosome profiling upon inhibition of eIF4A

Project description:Ribosome profiling of MDA-MB-231 cells treated with Silvestrol to monitor transcriptome wide, eIF4A-dependent changes in translation efficiency Translation efficiency (TE) of mRNAs dervied from ribosome footprints was monitored in the presence or absence of 25 nM Silvestrol, an inhibitor of eukaryotic translation initiation factor 4A (eIF4A). Transcripts with reduced TE in the presence of Silvestrol were compare to transcripts with reduced TE in the presence of INK128, a catalytic mTOR inhbitor.

2014-09-13 | E-GEOD-61375 | biostudies-arrayexpress

Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance.

Project description:Single cell transposon insertion site profiles were generated from A375 xenograft tumors that had aquired BRAF inhibitor resistance in vivo as a consequence of Sleeping Beauty transposon mutagenesis.

2024-01-17 | GSE232760 | GEO

Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A

Project description:Small molecule compounds that sense the nucleic acid sequences, promise the attractive venue for drug development. Such an unusual effect has been observed in the natural product Rocaglamide A (RocA) from Aglaia plant, proving to exhibit anti-tumor effects by clamping eukaryotic initiation factor (eIF) 4A onto mRNA polypurine sequences. Although eIF4A has been speculated the unique target of RocA, the insensitization of eIF4A in human cells only partially rescued the translation repression from RocA, suggesting another alternative target of this compound. Here, we revealed that DDX3 is an alternative target of RocA. Developing a RocA derivative with an O-nitrobenzoxadiazole unit (RocA-O-NBD), which can covalently bind to proximate proteins and provide fluorescence to them, we identified DDX3 bound to RocA. As observed in eIF4A, RocA locked the DDX3 protein onto polypurine sequences of RNA in an ATP-independent manner. De novo assembled Aglaia plant transcriptome uncovered the natural amino acid substitutions in Aglaia DDX3 to protect itself from RocA toxicity. Because of the dominant negative effect of RocA, we also proved the protein abundance of eIF4A and DDX3 in cancer cells determines their sensitivity to RocA. Overall, this study discovered DDX3 as another target of RocA and suggests the probability to predict tumor toxicity of RocA by the target abundance.

2020-12-07 | GSE148636 | GEO

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

Project description:The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of Silvestrol and related compounds. For example, eIF4A promotes T-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5'UTR sequences such as the 12-mer guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and Silvestrol-sensitive transcripts are a number of oncogenes, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5'UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase. Comparison of ribosome-protected RNA for drug treated and DMSO treated KOPT-K1 cell, two replicates of ribosome-protected RNA sequencing and three replicates of RNA-seq.

2014-07-27 | E-GEOD-56887 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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