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Series GSE87419 Query DataSets for GSE87419
Status Public on Jan 20, 2017
Title Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex (RNA-seq)
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment. In preclinical models MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation and p300 that drives transcriptional adaptation. Inhibition of P-TEFb associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts and syngeneic mouse TNBC models. Pharmacological targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.
Overall design 64 experimental samples; replicates are indicated in sample title
Contributor(s) Johnson GL, Zawistowski JS
Citation(s) 28108460
Submission date Sep 28, 2016
Last update date May 15, 2019
Contact name Gary L Johnson
Organization name University of North Carolina School of Medicine
Department Pharmacology
Lab Gary L. Johnson Lab
Street address 4009 Genetic Medicine Building, 120 Mason Farm Road
City Chapel Hill
State/province NC
ZIP/Postal code 27599
Country USA
Platforms (3)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (64)
GSM2330622 SUM229pos_DMSO_24h
GSM2330623 SUM229pos_30nMtrametinib_24h
GSM2330624 SUM229neg_DMSO_24h
This SubSeries is part of SuperSeries:
GSE87424 Enhancer Remodeling During Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacological Targeting of the P-TEFb Complex
BioProject PRJNA344725
SRA SRP090547

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE87419_DESeq2_Figure2_basal.xlsx 1.9 Mb (ftp)(http) XLSX
GSE87419_DESeq2_Figure2_claudin.xlsx 1.9 Mb (ftp)(http) XLSX
GSE87419_DESeq2_Figure2_subtype_group_comparison.xlsx 1.9 Mb (ftp)(http) XLSX
GSE87419_DESeq2_SUM159replicates.xlsx 1.3 Mb (ftp)(http) XLSX
GSE87419_RAW.tar 50.0 Mb (http)(custom) TAR (of CSV, TXT, XLSX)
GSE87419_SUM159_replicate2_normalizedRSEM.xlsx 1.0 Mb (ftp)(http) XLSX
GSE87419_SUM159_replicate3_normalizedRSEM.xlsx 1.0 Mb (ftp)(http) XLSX
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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