Drug-Induced Regulation of Target Expression

Murat Iskar,Michael Kuhn,Vera Van Noort,Lars Juhl Jensen,Peer Bork,Monica Campillos,Hiroaki Kitano

doi:10.1371/journal.pcbi.1000925

Abstract

Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention.

Highlights

For the future development of new drugs, the understanding of their mechanisms of action is vital
Many drug targets thought to be suitable for therapeutic purposes are subjected to positive or negative feedback loops upon chemical perturbations which might even account for the development of drug tolerance
We carried out the first systematic analysis of druginduced differential expression of drug targets using the Connectivity Map, a resource that contains the genomewide expression profiles of 1309 bioactive small molecules performed on four cultured human cells

Summary

Introduction

For the future development of new drugs, the understanding of their mechanisms of action is vital To tackle this in a large-scale, systemic way, the Connectivity Map (CMap) consortium studied the effects of 1309 bioactive small molecules including more than 800 marketed drugs on genome-wide gene expression in four cultured human cells, [1] (http://www.broadinstitute.org/cmap/). Drugs can perturb biological systems by interacting with different types of biomolecules [2], analysis of successful drugs has shown that generally they bind and alter the activity of proteins (so called drug targets). The essential data required for this data integration are provided by i) STITCH: a drug-target relations resource [6] and ii) the Connectivity Map (CMap) which contains genome-wide expression profiles of cells treated with small-molecules [1].

Author Summary

Findings

Materials and Methods