The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies
- Icahn School of Medicine at Mount Sinai, United States
- IBM Research, United States
- Columbia University, United States
Abstract
Our ability to discover effective drug combinations is limited, in part by insufficient understanding of how the transcriptional response of two monotherapies results in that of their combination. We analyzed matched time course RNAseq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. The sequential activation of transcription factors in time in the gene regulatory network was implicated. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.77 in the prediction of synergistic drug combinations in an independent dataset.
Data availability
Raw RNAseq data have been deposited in GEO under accession code GSE149428. Code is available at github.com/jennifereldiaz/drug-synergy.
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sub challenge 2, Drug Synergy PredictionSynapse, syn2785787.
Article and author information
Author details
Gustavo Stolovitzky
Funding
Internal funding from IBM Research and the Icahn School of Medicine at Mount Sinai to GS
- Jennifer EL Diaz
- Mehmet Eren Ahsen
- Thomas Schaffter
- Xintong Chen
- Bojan Losic
- Gustavo Stolovitzky
National Institutes of Health (NIH T32 GM007280)
- Jennifer EL Diaz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Alfonso Valencia, Barcelona Supercomputing Center - BSC, Spain
Version history
- Received: October 13, 2019
- Accepted: August 17, 2020
- Accepted Manuscript published: September 18, 2020 (version 1)
- Version of Record published: October 9, 2020 (version 2)
Copyright
© 2020, Diaz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies
eLife 9:e52707.
https://doi.org/10.7554/eLife.52707
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