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

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.

• Authors: A R R Maia, J de Man, U Boon, A Janssen, J-Y Song, M Omerzu, J G Sterrenburg, M B W Prinsen, N Willemsen-Seegers, J A D M de Roos, A M van Doornmalen, J C M Uitdehaag, G J P L Kops, J Jonkers, R C Buijsman, G J R Zaman, R H Medema
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 26 Issue 10 Pg. 2180-92 (Oct 2015) ISSN: 1569-8041 [Electronic] England
• PMID: 26153498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

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

Topics

• 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, mortality, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays