Correlating chemical sensitivity and basal gene expression reveals mechanism of action

By M. Rees, Brinton Seashore-Ludlow, Jaime H. Cheah, Drew J. Adams, Edmund V. Price, S. Gill, Sarah Javaid, Matthew E Coletti, V. Jones, Nicole E. Bodycombe and 17 more. Nature Chemical Biology, 2015

798 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/16a08bf3a75afd5a17af2df8c22f7548727e7edf

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Citations in the corpus

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15 (2017, methodology): “Data sets of indisulamAUC (area under the curve), basal gene expression, and copy number variation were described in (41).”
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CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy (2019, methodology): “To identify biomarkers of cell ferroptosis, we re-analyzed data from the Cancer Therapeutics Response Portal and evaluated correlations between gene expression profiles across 654 cancer cell lines and cell sensitivities to erastin and RSL3 16 .”