Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer

Overview

Journal Cancer Res

Specialty Oncology

Date 2017 Dec 13

PMID 29229604

Citations 113

Authors

Luz Garcia-Alonso

Francesco Iorio

Angela Matchan

Nuno Fonseca

Patricia Jaaks

Gareth Peat

Miguel Pignatelli

Fiammetta Falcone

Cyril H Benes

Ian Dunham

Graham Bignell

Simon S McDade

Mathew J Garnett

Julio Saez-Rodriguez

Affiliations

Soon will be listed here.

Abstract

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. 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. .

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