Inhibition of the spindle assembly checkpoint kinase TTK enhances the efficacy of docetaxel in a triple-negative breast cancer model
Maia, A. R R; De Man, J.; Boon, U.; Janssen, A.; Song, J. Y.; Omerzu, M.; Sterrenburg, J. G.; Prinsen, M. B W; Willemsen-Seegers, N.; De Roos, J. A D M; Van Doornmalen, A. M.; Uitdehaag, J. C M; Kops, G. J P L; Jonkers, J.; Buijsman, R. C.; Zaman, Guido J R; Medema, R. H.
(2015) Annals of Oncology, volume 26, issue 10, pp. 2180 - 2192
(Article)
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
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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.
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Keywords: 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, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Oncology, Hematology, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 0923-7534
Publisher: Oxford University Press
Note: © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
(Peer reviewed)