Drug Combination Antagonism and Single Agent Dominance Result from Differences in Death Activation Kinetics

Therapeutic regimens for cancer generally involve drugs used in combinations. Most prior work has focused on identifying and understanding synergistic drug-drug interactions; however, understanding sources of antagonistic interactions remains an important and understudied issue. To enrich for antagonistic interactions and reveal common features of these drug combinations, we screened all pairwise combinations of drugs characterized as canonical activators of different forms of regulated cell death. We find that this network is strongly enriched for antagonistic interactions, and in particular, enriched for an extreme form of antagonism, which we call \"single agent dominance\". Single agent dominance refers to antagonisms in which a two drug combination phenocopies one of the two agents. We find that dominance results from differences in the cell death onset time, with dominant drugs inducing death earlier and at faster rates than their suppressed counterparts. Finally, we explored the mechanisms by which parthanatotic agents dominate apoptotic agents, finding that dominance in this scenario is caused by mutually exclusive and conflicting use of PARP1. Taken together, our study reveals death activation kinetics as a predictive feature of antagonism, due to inhibitory crosstalk between cell death pathways.