Inhibition of the spindle assembly checkpoint kinase TTK enhances the efficacy of docetaxel in a triple-negative breast cancer model

Ann Oncol. 2015 Oct;26(10):2180-92. doi: 10.1093/annonc/mdv293. Epub 2015 Jul 7.

Abstract

Background: Triple-negative breast cancers (TNBC) are considered the most aggressive type of breast cancer, for which no targeted therapy exists at the moment. These tumors are characterized by having a high degree of chromosome instability and often overexpress the spindle assembly checkpoint kinase TTK. To explore the potential of TTK inhibition as a targeted therapy in TNBC, we developed a highly potent and selective small molecule inhibitor of TTK, NTRC 0066-0.

Results and conclusions: The compound is characterized by long residence time on the target and inhibits the proliferation of a wide variety of human cancer cell lines with potency in the same range as marketed cytotoxic agents. In cell lines and in mice, NTRC 0066-0 inhibits the phosphorylation of a TTK substrate and induces chromosome missegregation. NTRC 0066-0 inhibits tumor growth in MDA-MB-231 xenografts as a single agent after oral application. To address the effect of the inhibitor in breast cancer, we used a well-defined mouse model that spontaneously develops breast tumors that share key morphologic and molecular features with human TNBC. Our studies show that combination of NTRC 0066-0 with a therapeutic dose of docetaxel resulted in doubling of mouse survival and extended tumor remission, without toxicity. Furthermore, we observed that treatment efficacy is only achieved upon co-administration of the two compounds, which suggests a synergistic in vivo effect. Therefore, we propose TTK inhibition as a novel therapeutic target for neoadjuvant therapy in TNBC.

Keywords: TTK/Mps1 kinase inhibitor; chromosome missegregation; docetaxel; increased survival; triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Proliferation / drug effects*
  • Disease Models, Animal
  • Docetaxel
  • Drug Therapy, Combination
  • Female
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Molecular Structure
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Survival Rate
  • Taxoids / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Taxoids
  • Docetaxel
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • TTK protein, human