Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer
| Autor: | Patricia Jaaks, Julio Saez-Rodriguez, Luz Garcia-Alonso, Cyril H. Benes, Nuno A. Fonseca, Graham R. Bignell, Simon S. McDade, Angela Matchan, Fiammetta Falcone, Ian Dunham, Gareth Peat, Miguel Pignatelli, Mathew J. Garnett, Francesco Iorio |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Antineoplastic Agents Apoptosis Computational biology Biology Article Small Molecule Libraries Small hairpin RNA 03 medical and health sciences SDG 3 - Good Health and Well-being Neoplasms Gene expression Journal Article Biomarkers Tumor Tumor Cells Cultured medicine Humans Transcription factor Cell Proliferation Regulation of gene expression Cell growth Cancer medicine.disease 3. Good health Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Pharmacogenetics Pharmacogenomics Transcription Factors |
| Zdroj: | Garcia-Alonso, L M, Iorio, F, Matchan, A, Fonseca, N A, Jaaks, P, Peat, G, Pignatelli, M, Falcone, F, Benes, C H, Dunham, I, Bignell, G R, McDade, S, Garnett, M J & Saez-Rodriguez, J 2017, ' Transcription factor activities enhance markers of drug sensitivity in cancer ', Cancer Research, vol. 78, no. 3, pp. 1-35 . https://doi.org/10.1158/0008-5472.CAN-17-1679 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-17-1679 |
| Popis: | 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. Cancer Res; 78(3); 769–80. ©2017 AACR. |
| Databáze: | OpenAIRE |
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