Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer

被引：125

作者：

Garcia-Alonso, Luz ^{[1
,2
]}

Iorio, Francesco ^{[1
,2
]}

Matchan, Angela ^{[2
,3
]}

Fonseca, Nuno ^{[1
]}

Jaaks, Patricia ^{[3
]}

Peat, Gareth ^{[1
,2
]}

Pignatelli, Miguel ^{[1
,2
]}

Falcone, Fiammetta ^{[4
]}

Benes, Cyril H. ^{[5
]}

Dunham, Ian ^{[1
,2
]}

Bignell, Graham ^{[2
,3
]}

McDade, Simon S. ^{[4
]}

Garnett, Mathew J. ^{[2
,3
]}

Saez-Rodriguez, Julio ^{[1
,2
,6
]}

机构：

[1] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge, England

[2] OpenTargets, Wellcome Genome Campus, Cambridge, England

[3] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge, England

[4] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland

[5] Massachusetts Gen Hosp, Boston, MA 02114 USA

[6] Rhein Westfal TH Aachen, Fac Med, Joint Res Ctr Computat Biomed JRC COMBINE, Aachen, Germany

来源：

CANCER RESEARCH | 2018年 / 78卷 / 03期

基金：

英国惠康基金;

关键词：

GENE NETWORK INFERENCE; DEPENDENT PATHWAY; PROTEIN; EXPRESSION; MUTATIONS; GENOME; P53; LANDSCAPE; SURVIVAL; REVEALS;

D O I：

10.1158/0008-5472.CAN-17-1679

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analyzing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anticancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea. opentargets. io, offer a broad foundation for discovering opportunities to refine personalized cancer therapies. Significance: Systematic analysis of transcriptional dysregulation in cancer cell lines and patient tumor specimens offers a publicly searchable foundation to discover new opportunities to refine personalized cancer therapies. (C) 2017 AACR.

引用

页码：769 / 780

页数：12

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