Encircling the regions of the pharmacogenomic landscape that determine drug response

Background: The integration of large-scale drug sensitivity screens and genome-wide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for previous knowledge about drug action. In particular, transcriptional signatures of drug sensitivity may guide drug repositioning, prioritize drug combinations, and point to new therapeutic biomarkers. However, the inherent complexity of transcriptional signatures, with thousands of differentially expressed genes, makes them hard to interpret, thus giving poor mechanistic insights and hampering translation to clinics. Methods: To simplify drug signatures, we have developed a network-based methodology to identify functionally coherent gene modules. Our strategy starts with the calculation of drug-gene correlations and is followed by a pathway-oriented filtering and a network-diffusion analysis across the interactome. Results: We apply our approach to 189 drugs tested in 671 cancer cell lines and observe a connection between gene expression levels of the modules and mechanisms of action of the drugs. Further, we characterize multiple aspects of the modules, including their functional categories, tissue-specificity, and prevalence in clinics. Finally, we prove the predictive capability of the modules and demonstrate how they can be used as gene sets in conventional enrichment analyses. Conclusions: Network biology strategies like module detection are able to digest the outcome of large-scale pharmacogenomic initiatives, thereby contributing to their interpretability and improving the characterization of the drugs screened.A.F-T. is a recipient of an FPI fellowship. P.A. acknowledges the support of the Spanish Ministerio de Economía y Competitividad (BIO2016-77038-R) and the European Research Council (SysPharmAD: 614944)