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Series GSE87418 Query DataSets for GSE87418
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 (ChIP-seq)
Organism Homo sapiens
Experiment type Genome binding/occupancy 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 44 experimental samples analyzed, one chromatin input control sample for each cell line
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 (2)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (61)
GSM2330549 SUM159_BRD4_DMSO_24h
GSM2330550 SUM159_BRD4_100nMtrametinib_24h
GSM2330551 SUM159_BRD4_300nMJQ1_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 PRJNA344724
SRA SRP090546

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

Supplementary file Size Download File type/resource
GSE87418_Figure7_peakclassification.xlsx 8.6 Mb (ftp)(http) XLSX
GSE87418_RAW.tar 93.5 Mb (http)(custom) TAR (of BED)
GSE87418_SupplementaryTableS4_peakclassification.xlsx 8.4 Mb (ftp)(http) XLSX
GSE87418_SupplementaryTableS5_peakclassification.xlsx 4.2 Mb (ftp)(http) XLSX
GSE87418_peakclassification_SUM229neg.xlsx 5.0 Mb (ftp)(http) XLSX
GSE87418_peakclassification_SUM229pos.xlsx 5.0 Mb (ftp)(http) XLSX
GSE87418_peakclassification_bortezomib.xlsx 7.2 Mb (ftp)(http) XLSX
GSE87418_peakclassification_shMYC.xlsx 7.6 Mb (ftp)(http) XLSX
GSE87418_peakclassification_trametinib_timecourse.xlsx 7.5 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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