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Series GSE89128 Query DataSets for GSE89128
Status Public on Oct 23, 2017
Title Suppression of adaptive responses to targeted cancer therapy by transcriptional repression [ChIP-seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Large-scale genomic profiling efforts have facilitated the characterization of molecular alterations in cancers and aided the development of targeted kinase inhibitors for a wide array of cancer types. However, resistance to these targeted therapies invariably develops and limits their clinical efficacy. Targeting tumours with kinase inhibitors induces complex adaptive survival programs that promote the persistence of a fraction of the original cancer cell population, facilitating the eventual outgrowth of inhibitor-resistant tumour clones following clonal evolution. Here we show that the addition of a newly identified transcriptional repressor, THZ1, to targeted cancer therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in cellular and in vivo cancer models with diverse genetic dependencies. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant. THZ1 can exploit this dependency by blocking dynamic transcriptional responses, remodelling of enhancers and key signalling outputs required for tumour cell survival in the setting of targeted cancer therapies. These findings suggest that the addition of THZ1 to targeted cancer therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.
 
Overall design ChIP-Seq for enhancer-binding proteins in multiple tumor cell lines
 
Contributor(s) Rusan M, Li K, Li Y, Christensen CL, Abraham BJ, Kwiatkowski N, Buczkowski KA, Bockorny B, Chen T, Li S, Rhee K, Zhang H, Chen W, Terai H, Tavares T, Zhang T, Kim TJ, Hong S, Neupane NP, Silkes M, Mudianto T, Tan L, Shimamura T, Meyerson M, Watanabe H, Gray NS, Young RA, Wong K, Hammerman PS
Citation(s) 29054992
Submission date Oct 24, 2016
Last update date May 15, 2019
Contact name Richard A Young
E-mail(s) young_computation@wi.mit.edu
Phone 617-258-5219
Organization name Whitehead Institute for Biomedical Research
Lab Young Lab
Street address 9 Cambridge Center
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
 
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (76)
GSM2359435 1_A375 DMSO_BRD4 [lab: Hammerman-DFCI]
GSM2359436 2_A375 THZ1_BRD4 [lab: Hammerman-DFCI]
GSM2359437 3_A375 RTKi_BRD4 [lab: Hammerman-DFCI]
This SubSeries is part of SuperSeries:
GSE89129 Suppression of adaptive responses to targeted cancer therapy by transcriptional repression
Relations
BioProject PRJNA350359
SRA SRP092083

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
GSE89128_RAW.tar 5.8 Gb (http)(custom) TAR (of WIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
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