Correlating chemical sensitivity and basal gene expression reveals mechanism of action

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.

Divergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity

“…To account for these differences and determine where treatment with HDACi may be beneficial, diagnostic indicators of HDACi efficacy are needed. While several genomic approaches correlating HDACi response with mutational landscape or changes in basal gene expression serve as invaluable tools to identify prognostic markers associated with HDACi efficacy (Rees et al, 2016, Garnett et al, 2012), our study compliments this approach by identifying direct changes in HDAC binding, selectivity and enzymatic activity, which may also affect HDACi efficacy.…”

Targeting Cancer Stem Cells with Small Molecules

“…[27] Looking at gene expression profiles of breast cancer cells treated with ML239, NF-kB (nuclear factor kappa-light-chainenhancer of activated B cells), a protein complex that is implicated in transcription and cytokine production, was significantly altered. [28] It was subsequently argued that ML239 acts mainly through activation of FADS2 (fatty acid desaturase 2), [29] supporting the notion that metabolic states of CSCs can potentially be exploited for therapeutic purposes. Other classes of molecules, such as cinnamides, [15b] were also identified to target CSCs using the HMLER model, highlighting the power of unbiased approaches in the context of CSCs where little is known about a potential Achilles' heel.…”

The Analysis of Anticancer Drug Sensitivity of Lung Cancer Cell Lines by using Machine Learning Clustering Techniques

“…Natural herbal products are used in traditional medicine, and it is currently considered in anticancer activities [36], [37]. These activity indexes, apoptosis stimulation and antiproliferative activities [38], as research has shown that these natural healing products had no side effects, or as minimum side effects were much more reasonable compared with that chemotherapeutic [39].…”