A mammalian functional-genetic approach to characterizing cancer therapeutics

• Main Authors: Williams, Richard T. (Author), Jiang, Hai (Contributor), Hemann, Michael (Contributor), Pritchard, Justin R. (Author), Lauffenburger, Douglas A (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Lauffenburger, Douglas A. (Contributor), Pritchard, Justin Robert (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2011-11-16T22:27:33Z.
• Subjects: Article
• Online Access: Get fulltext

Supplementary information is available online at http://www.nature.com/naturechemicalbiology/. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/.
Identifying mechanisms of drug action remains a fundamental impediment to the development and effective use of chemotherapeutics. Here we describe an RNA interference (RNAi)-based strategy to characterize small-molecule function in mammalian cells. By examining the response of cells expressing short hairpin RNAs (shRNAs) to a diverse selection of chemotherapeutics, we could generate a functional shRNA signature that was able to accurately group drugs into established biochemical modes of action. This, in turn, provided a diversely sampled reference set for high-resolution prediction of mechanisms of action for poorly characterized small molecules. We could further reduce the predictive shRNA target set to as few as eight genes and, by using a newly derived probability-based nearest-neighbors approach, could extend the predictive power of this shRNA set to characterize additional drug categories. Thus, a focused shRNA phenotypic signature can provide a highly sensitive and tractable approach for characterizing new anticancer drugs.
National Institute of Mental Health (U.S.) (grant RO1 CA128803-03)
American Association for Cancer Research
Massachusetts Institute of Technology. Dept. of Biology
National Cancer Institute (U.S.). Integrative Cancer Biology Program (grant 1-U54-CA112967)