%0 Journal Article %A Luz Garcia-Alonso %A Francesco Iorio %A Angela Matchan %A Nuno Fonseca %A Patricia Jaaks %A Fiamenta Falcone %A Graham Bignell %A Simon S. McDade %A Mathew J. Garnett %A Julio Saez-Rodriguez %T Transcription factor activities enhance markers of drug response in cancer %D 2017 %R 10.1101/129478 %J bioRxiv %P 129478 %X Transcriptional dysregulation is a key feature of cancer. Transcription factors (TFs) are the main link between signalling pathways and the transcriptional regulatory machinery of the cell, positioning them as key oncogenic inductors and therefore potential targets of therapeutic intervention. We implemented a computational pipeline to infer TF regulatory activities from basal gene expression and applied it to publicly available and newly generated RNA-seq data from a collection of 1,010 cancer cell lines and 9,250 primary tumors. We show that the predicted TF activities recapitulate known mechanisms of transcriptional dysregulation in cancer and dissect mutant-specific effects in driver genes. Importantly, we show the potential for predicted TF activities to be used as markers of sensitivity to the inhibition of their upstream regulators. Furthermore, combining these inferred activities with existing pharmacogenomic markers significantly improves the stratification of sensitive and resistant cell lines for several compounds. Our approach provides a framework to link driver genomic alterations with transcriptional dysregulation that helps to predict drug sensitivity in cancer and to dissect its mechanistic determinants.ACCAdrenocortical carcinomaALLAcute myeloid leukemiaBLCABladder carcinomaBRCABreast carcinomaCCLECancer Cell Lines EncyclopediaCESCCervical squamous carcinomaChIPChromatin immunoprecipitationChIP-XChromatin immunoprecipitation coupled with high-throughput techniqueCNACopy number alterationCOREAD(COAD/READ) Colon adenocarcinoma/Rectal adenocarcinomaCTFRConsensus transcription factor regulonDLBCDifuse B cell lymphomaEMTEpithelial-mesenchymal transitionFDRFalse discovery rateFETFisher’s exact testGBMGlioblastoma multiformeGDSCGenomics of Drug Sensitivity in CancerHNSCHead and neck squamous cell carcinomaKICHKidney chromophomeKIRCKidney renal clear cell carcinomaKIRPKidney renal papillary carcinomaLAMLAcute myeloid leukemiaLGGLower grade gliomaLIHCLiver hepatocarcinomaLUADLung adenocarcinomaLUSCLung squamous cell carcinomaMBMedulloblastomaMMMyelomaNSCLCNon-Small cell lung carcinomaOVSerous ovarian adenocarcinomaPRADProstate adenocarcinomaSKCMSkin carcinomaSTADStomach adenocarcinomaTCGAThe Cancer Genome AtlasTFTranscription factorTFBSTranscription factor binding siteTHCAThyroid carcinomaUCECUterine corpus endometrioid carcinomaWESWhole exome sequencing %U https://www.biorxiv.org/content/biorxiv/early/2017/04/21/129478.full.pdf