Universität zu Köln

Lukacisin, Martin ORCID: 0000-0001-6549-4177 and Bollenbach, Tobias ORCID: 0000-0003-4398-476X (2019). Emergent Gene Expression Responses to Drug Combinations Predict Higher-Order Drug Interactions. Cell Syst., 9 (5). S. 423 - 437. CAMBRIDGE: CELL PRESS. ISSN 2405-4720

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Abstract

Effective design of combination therapies requires understanding the changes in cell physiology that result from drug interactions. Here, we show that the genome-wide transcriptional response to combinations of two drugs, measured at a rigorously controlled growth rate, can predict higher-order antagonism with a third drug in Saccharomyces cerevisiae. Using isogrowth profiling, over 90% of the variation in cellular response can be decomposed into three principal components (PCs) that have clear biological interpretations. We demonstrate that the third PC captures emergent transcriptional programs that are dependent on both drugs and can predict antagonism with a third drug targeting the emergent pathway. We further show that emergent gene expression patterns are most pronounced at a drug ratio where the drug interaction is strongest, providing a guideline for future measurements. Our results provide a readily applicable recipe for uncovering emergent responses in other systems and for higher-order drug combinations. A record of this paper's transparent peer review process is included in the Supplemental Information.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lukacisin, Martin UNSPECIFIED orcid.org/0000-0001-6549-4177 UNSPECIFIED Bollenbach, Tobias UNSPECIFIED orcid.org/0000-0003-4398-476X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-127039
DOI:	10.1016/j.cels.2019.10.004
Journal or Publication Title:	Cell Syst.
Volume:	9
Number:	5
Page Range:	S. 423 - 437
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2405-4720
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Physics > Institut für Biologische Physik
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LITHIUM; INHIBITION; TARGET; GROWTH; DYNAMICS; CELLS; YEAST Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12703