Abstract 1638: Preclinical characterization of the novel TTK kinase inhibitor S81694 for the treatment of triple negative breast cancer
Authors: Riccardo Colombo, Mike Burbridge, Marianne Rodriguez, Frédérique Cantero, Marina Caldarelli, Maria Laura Giorgini, Francesco Sola, Dario Ballinari, Marina Ciomei, Roberta Bosotti, Alessia Montagnoli, Antonella Isacchi, Daniele Donati, Arturo Galvani
Journal: Cancer Research (2015)

Abstract The tyrosine threonine kinase TTK, also known as Monopolar Spindle 1 kinase (MPS1), is a conserved kinase found to be highly expressed in a number of human tumors of different origin. TTK kinase activity plays a critical role in the control of mitosis, regulating the spindle assembly checkpoint (SAC), a mitotic mechanism required for proper chromosome alignment and segregation during cellular division. The activity of this checkpoint has been shown to be proficient and up-regulated in aneuploid tumors, a common feature measured in approximately 90% of solid tumors and 70% of hematological cancers. S81694 (NMS-P153) is a novel potent inhibitor of TTK. It is a tight binder compound with long residence time on the target and is highly selective for TTK against a wide range of tested enzymes (kinases, channels, hormones, GPCRs). In vitro, brief exposure is sufficient to commit cells to death with the compound showing anti-proliferative activity with a demonstrated mechanism of action and marked tumor growth inhibition in preclinical in vivo tumor models associated with a good pharmacokinetic profile in both rodent and non-rodent species. TTK inhibitors are anticipated to be more active in SAC dependent tumors and data in the literature suggests that triple negative breast cancer is among the tumor types potentially highly dependent on TTK activity. Moreover, in accelerating mitosis, TTK inhibitors have a novel mode of action as compared to currently known mitotic inhibitors. To confirm the role of TTK in breast cancer and identify a sensitive patient population to S81694 treatment, translational studies have been conducted on a large panel of human tumor cell lines, including 39 of mammary gland origin. Anti-proliferative activity was measured after 72h continuous treatment or after a brief treatment of 7h followed by 2D colony forming assay to verify the long term effects of a treatment which mimics compound half-life in mice. In addition, active caspase 3 induction was also analyzed to identify cell lines more prone to activate apoptosis upon treatment. Triple negative breast cancer (TNBC) cell lines were confirmed to be particularly sensitive to S81694 and correlation was observed between sensitivity profile in vitro and tumor growth inhibition in vivo. In MDA-MB-231 xenograft and orthotopic models, tumor regression, cured animals and metastasis reduction in several organs including brain and lungs was observed. These results further confirm the role of TTK in triple negative breast cancer and could support the clinical development of S81694 in this indication. Citation Format: Riccardo Colombo, Mike Burbridge, Marianne Rodriguez, Frédérique Cantero, Marina Caldarelli, Maria Laura Giorgini, Francesco Sola, Dario Ballinari, Marina Ciomei, Roberta Bosotti, Alessia Montagnoli, Antonella Isacchi, Daniele Donati, Arturo Galvani. Preclinical characterization of the novel TTK kinase inhibitor S81694 for the treatment of triple negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1638. doi:10.1158/1538-7445.AM2015-1638