title: A mammalian functional-genetic approach to characterizing cancer therapeutics.
abstract: 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.
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Jiang
authors.forename: Justin R
authors.initials: JR
authors.lastname: Pritchard
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
mesh_terms: D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference