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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Source data for evaluation of the mechanism by which drugs led to cell death are included in Supplementary Dataset 1. Source data for the drug combination screen in Fig. 2d are included in Supplementary Dataset th2. PCA score data related to Fig. 4a–c are included in Supplementary Dataset 3. The list of 130 SAD combinations identified in this study is included in Supplementary Dataset 4. All other data are available upon request.
Custom analysis code for computing LF kinetics from endpoint data is included in the MATLAB script ‘backfitting and LED.m’. Other analysis code is available upon request.
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We thank current and past members of the Lee labotatory and all members of PSB for their helpful comments and critiques during the execution of this study. In addition, we thank M. Walhout, J. Dekker, A. Mitchell and J. Pritchard for their thoughtful comments during the preparation of this manuscript. The px330-puro-hSpCas9 plasmid was a kind gift from T. Fazzio (UMass Medical School). This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (R01GM127559 to M.J.L.); the American Cancer Society (RSG-17-011-01 to M.J.L.); and an NIH/NCI training grant (Translational Cancer Biology Training Grant, T32-CA130807 to R.R., B.D.L. and P.C.G.).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1–14 and Supplementary Tables 1–3.
Drug responses in U2OS WT and DKO cells.
Combination drug screen.
PCA scores for drugs and drug combinations.
SAD combinations in U2OS cells.
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Richards, R., Schwartz, H.R., Honeywell, M.E. et al. Drug antagonism and single-agent dominance result from differences in death kinetics. Nat Chem Biol 16, 791–800 (2020). https://doi.org/10.1038/s41589-020-0510-4
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