Large-scale elucidation of drug response pathways in humans.
Elucidating signaling pathways is a fundamental step in understanding cellular processes and developing new therapeutic strategies. Here we introduce a method for the large-scale elucidation of signaling pathways involved in cellular response to drugs. Combining drug targets, drug response expression profiles, and the human physical interaction network, we infer 99 human drug response pathways and study their properties. Based on the newly inferred pathways, we develop a pathway-based drug-drug similarity measure and compare it to two common, gold standard drug-drug similarity measures. Remarkably, our measure provides better correspondence to these gold standards than similarity measures that are based on associations between drugs and known pathways, or on drug-specific gene expression profiles. It further improves the prediction of drug side effects and indications, elucidating specific response pathways that may be associated with these drug properties. Supplementary Material for this article is available at www.liebertonline.com/cmb.
Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel.
Yael
Y
Silberberg
Assaf
A
Gottlieb
Martin
M
Kupiec
Eytan
E
Ruppin
Roded
R
Sharan
D000465:Algorithms; D019540:Area Under Curve; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D064420:Drug-Related Side Effects and Adverse Reactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016013:Likelihood Functions; D008954:Models, Biological; D060066:Protein Interaction Maps; D012372:ROC Curve; D015398:Signal Transduction / Q000187:drug effects*; D060388:Support Vector Machine; D015854:Up-Regulation
D004268:DNA-Binding Proteins