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Nat Chem Biol DOI:10.1038/nchembio.1986

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

Publication TypeJournal Article
Year of Publication2016
AuthorsRees, MG, Seashore-Ludlow, B, Cheah, JH, Adams, DJ, Price, EV, Gill, S, Javaid, S, Coletti, ME, Jones, VL, Bodycombe, NE, Soule, CK, Alexander, B, Li, A, Montgomery, P, Kotz, JD, C Hon, S-Y, Munoz, B, Liefeld, T, Dančík, V, Haber, DA, Clish, CB, Bittker, JA, Palmer, M, Wagner, BK, Clemons, PA, Shamji, AF, Schreiber, SL
JournalNat Chem Biol
Date Published2016 Feb
KeywordsAflatoxins, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Computer Simulation, Drug Delivery Systems, Female, Gene Expression Regulation, Neoplastic, Humans, Molecular Structure, Principal Component Analysis, Real-Time Polymerase Chain Reaction, Small Molecule Libraries

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.


Alternate JournalNat. Chem. Biol.
PubMed ID26656090
PubMed Central IDPMC4718762
Grant List / / Howard Hughes Medical Institute / United States
U01 CA176152 / CA / NCI NIH HHS / United States
U01CA176152 / CA / NCI NIH HHS / United States