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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Antagonism
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Kinetics
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Parthanatos / drug effects*
  • Parthanatos / genetics
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism

Substances

  • Antineoplastic Agents
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1