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  3. Correlating chemical sensitivity and basal gene expression reveals mechanism of action

Correlating chemical sensitivity and basal gene expression reveals mechanism of action

  • Nat Chem Biol. 2016 Feb;12(2):109-16. doi: 10.1038/nchembio.1986.
Matthew G Rees 1,  Brinton Seashore-Ludlow 1 2,  Jaime H Cheah 1 2,  Drew J Adams 1 2,  Edmund V Price 1 2,  Shubhroz Gill 1,  Sarah Javaid 3,  Matthew E Coletti 1,  Victor L Jones 1,  Nicole E Bodycombe 1 2,  Christian K Soule 1 2,  Benjamin Alexander 1,  Ava Li 1,  Philip Montgomery 1,  Joanne D Kotz 1,  C Suk-Yee Hon 1,  Benito Munoz 1,  Ted Liefeld 1 2,  Vlado Dančík 1,  Daniel A Haber 3,  Clary B Clish 1,  Joshua A Bittker 1,  Michelle Palmer 1 2,  Bridget K Wagner 1,  Paul A Clemons 1,  Alykhan F Shamji 1,  Stuart L Schreiber 1
Affiliations

Affiliations

  • 1 Broad Institute, Cambridge, Massachusetts, USA.
  • 2 Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden (B.S.L); Koch Institute for Cancer Research at MIT, Cambridge, Massachusetts, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Novartis Institutes for Biomedical Research, Emeryville, California, USA; Pfizer, Cambridge, Massachusetts, USA; University of California San Diego School of Medicine, La Jolla, California, USA; ImmunoGen, Waltham, Massachusetts, USA.
  • 3 Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
PMID: 26656090 DOI: 10.1038/nchembio.1986
Abstract

Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ∼19,000 basal transcript levels across 823 different human Cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast Cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.

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