VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells

Cell Syst. 2019 Jul 24;9(1):74-92.e8. doi: 10.1016/j.cels.2019.05.009. Epub 2019 Jul 10.

Abstract

There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, an MTH1 inhibitor that prevents detoxification of oxidized nucleotide triphosphates. This combination showed robust synergistic killing of cancer, but not normal, cells that, surprisingly, was MTH1-independent. To dissect the underlying synergistic mechanism, we developed VISAGE, a strategy integrating experimental synergy quantification with computational-pathway-based gene expression analysis. VISAGE predicted, and we experimentally confirmed, that this synergistic combination treatment targeted the mitotic spindle. Specifically, TH588 binding to β-tubulin impaired microtubule assembly, which when combined with Plk1 blockade, synergistically disrupted mitotic chromosome positioning to the spindle midzone. These findings identify a cancer-specific mitotic vulnerability that is targetable using Plk1 inhibitors with microtubule-destabilizing agents and highlight the general utility of the VISAGE approach to elucidate molecular mechanisms of drug synergy.

Keywords: MTH1; Plk1; TH588; anti-microtubule drugs; cancer therapy; chromosome alignment; chromosome congression; drug synergy; mitosis; tubulin.

Publication types

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

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line, Tumor
  • Computational Biology
  • DNA Repair Enzymes / antagonists & inhibitors
  • Drug Synergism
  • Gene Expression Profiling
  • Growth Inhibitors / therapeutic use*
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Pyrimidines / therapeutic use*
  • Spindle Apparatus / drug effects*
  • Spindle Apparatus / physiology
  • Tubulin / metabolism

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Growth Inhibitors
  • Proto-Oncogene Proteins
  • Pyrimidines
  • TH588 compound
  • Tubulin
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • Phosphoric Monoester Hydrolases
  • 8-oxodGTPase
  • DNA Repair Enzymes