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|Ref Type||Journal Article|
|Authors||Maia AR, de Man J, Boon U, Janssen A, Song JY, Omerzu M, Sterrenburg JG, Prinsen MB, Willemsen-Seegers N, de Roos JA, van Doornmalen AM, Uitdehaag JC, Kops GJ, Jonkers J, Buijsman RC, Zaman GJ, Medema RH|
|Title||Inhibition of the spindle assembly checkpoint kinase TTK enhances the efficacy of docetaxel in a triple-negative breast cancer model.|
|Journal||Annals of oncology : official journal of the European Society for Medical Oncology|
|Abstract Text||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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|NTRC 0066-0||SB19776||MPS1 Inhibitor 25||NTRC 0066-0 inhibits TTK (MPS1) activity thereby preventing cell proliferation (PMID: 26153498, PMID: 28539250).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||Docetaxel + NTRC 0066-0||Preclinical||Actionable||In a preclinical study, the TTK (MPS1) inhibitor, NTRC 0066-0, acted in synergy with docetaxel to induce tumor remission and increase survival of TNBC mouse models (PMID: 26153498).||26153498|
|Unknown unknown||breast cancer||not applicable||NTRC 0066-0||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the TTK (MPS1) inhibitor, NTRC 0066-0, prevented tumor growth in breast cancer cell line xenograft models (PMID: 26153498).||26153498|