title: 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.
  
  
  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.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam.
authors.forename: A R R
authors.initials: AR
authors.lastname: Maia
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: J
authors.initials: J
authors.lastname: de Man
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre.
authors.forename: U
authors.initials: U
authors.lastname: Boon
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam.
authors.forename: A
authors.initials: A
authors.lastname: Janssen
authors.affiliation: Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Song
authors.affiliation: Department of Medical Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Omerzu
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: J G
authors.initials: JG
authors.lastname: Sterrenburg
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: M B W
authors.initials: MB
authors.lastname: Prinsen
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: N
authors.initials: N
authors.lastname: Willemsen-Seegers
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: J A D M
authors.initials: JA
authors.lastname: de Roos
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: A M
authors.initials: AM
authors.lastname: van Doornmalen
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: J C M
authors.initials: JC
authors.lastname: Uitdehaag
authors.affiliation: Department of Medical Oncology Department of Cancer Genomics Netherlands, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: G J P L
authors.initials: GJ
authors.lastname: Kops
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre Department of Cancer Genomics Netherlands, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Netherlands Translational Research Center B.V., Oss.
authors.forename: R C
authors.initials: RC
authors.lastname: Buijsman
authors.affiliation: Netherlands Translational Research Center B.V., Oss guido.zaman@ntrc.nl.
authors.forename: G J R
authors.initials: GJ
authors.lastname: Zaman
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam Department of Cancer Genomics Netherlands, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D000077143:Docetaxel; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D043823:Taxoids / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: TTK/Mps1 kinase inhibitor; chromosome missegregation; docetaxel; increased survival; triple-negative breast cancer