Pan-Cancer Drug Sensitivity Prediction from Gene Expression using Deep Learning

Cancer is a group of complex diseases, with tumor heterogeneity, durable drug efficacy, emerging resistance, and host toxicity presenting major challenges to the development of effective cancer therapeutics. While traditionally used methods have remained limited in their capacity to overcome these challenges in cancer drug development, efforts have been made in recent years toward applying "big data" to cancer research and precision oncology. By curating, standardizing, and integrating data from various databases, we developed deep learning architectures that use perturbation and baseline transcriptional signatures to predict efficacious small molecule compounds and genetic dependencies in cancer. A series of internal validations followed by prospective validation in prostate cancer cell lines were performed to ensure consistent performance and model applicability. We report SensitivitySeq, a novel bioinformatics tool for prioritizing small molecule compounds and gene dependencies in silico to drive the development of targeted therapies for cancer. To the best of our knowledge, this is the first supervised deep learning approach, validated in vitro, to predict drug sensitivity using baseline cancer cell line gene expression alongside cell line-independent perturbation-response consensus signatures. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/623715v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@9f48bcorg.highwire.dtl.DTLVardef@16056f7org.highwire.dtl.DTLVardef@1ed9095org.highwire.dtl.DTLVardef@1af3fce_HPS_FORMAT_FIGEXP M_FIG C_FIG