Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 7, Pages 791-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0510-4
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Funding
- National Institute of General Medical Sciences of the National Institutes of Health [R01GM127559]
- American Cancer Society [RSG-17-011-01]
- NIH/NCI training grant (Translational Cancer Biology Training Grant) [T32-CA130807]
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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.
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