University of Massachusetts Medical School Faculty Publications

Title

Drug antagonism and single-agent dominance result from differences in death kinetics

UMMS Affiliation

Program in Systems Biology; Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences

Publication Date

2020-07-01

Document Type

Article

Disciplines

Biochemistry, Biophysics, and Structural Biology | Cancer Biology | Cell Biology | Medicinal Chemistry and Pharmaceutics | Neoplasms | Systems Biology

Abstract

Cancer treatment generally involves drugs used in combinations. Most previous work has focused on identifying and understanding synergistic drug-drug interactions; however, understanding antagonistic interactions remains an important and understudied issue. To enrich for antagonism and reveal common features of these combinations, we screened all pairwise combinations of drugs characterized as activators of regulated cell death. This network is strongly enriched for antagonism, particularly a form of antagonism that we call 'single-agent dominance'. Single-agent dominance refers to antagonisms in which a two-drug combination phenocopies one of the two agents. Dominance results from differences in cell death onset time, with dominant drugs acting earlier than their suppressed counterparts. We explored mechanisms by which parthanatotic agents dominate apoptotic agents, finding that dominance in this scenario is caused by mutually exclusive and conflicting use of Poly(ADP-ribose) polymerase 1 (PARP1). Taken together, our study reveals death kinetics as a predictive feature of antagonism, due to inhibitory crosstalk between cell death pathways.

Keywords

Cell death, High-throughput screening, Small molecules, Systems biology

DOI of Published Version

10.1038/s41589-020-0510-4

Source

Richards R, Schwartz HR, Honeywell ME, Stewart MS, Cruz-Gordillo P, Joyce AJ, Landry BD, Lee MJ. Drug antagonism and single-agent dominance result from differences in death kinetics. Nat Chem Biol. 2020 Jul;16(7):791-800. doi: 10.1038/s41589-020-0510-4. Epub 2020 Apr 6. PMID: 32251407; PMCID: PMC7311243. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Nature chemical biology

PubMed ID

32251407

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