A mammalian functional-genetic approach to characterizing cancer therapeutics.

TitleA mammalian functional-genetic approach to characterizing cancer therapeutics.
Publication TypeJournal Article
Year of Publication2011
AuthorsJiang, H, Pritchard, JR, Williams, RT, Lauffenburger, DA, Hemann, MT
JournalNat Chem Biol
Volume7
Issue2
Pagination92-100
Date Published2011 Feb
ISSN1552-4469
KeywordsHumans, Neoplasms, Phenotype, RNA Interference
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.

DOI10.1038/nchembio.503
Alternate JournalNat. Chem. Biol.
PubMed ID21186347
PubMed Central IDPMC3070540
Grant ListR01 CA128803-03 / CA / NCI NIH HHS / United States
R01 CA128803-03 / CA / NCI NIH HHS / United States
R01 CA128803-04 / CA / NCI NIH HHS / United States
U54 CA112967-03 / CA / NCI NIH HHS / United States
U54-CA112967 / CA / NCI NIH HHS / United States