Abstract B065: TTK inhibitors as a targeted therapy for β-catenin mutant cancers

Abstract

Abstract The dual-specificity protein kinase TTK, commonly referred to as Mps1, is a component of the spindle assembly checkpoint, a surveillance mechanism that ensures the fidelity of chromosome segregation. Inhibition of TTK kinase activity with small molecule kinase inhibitors leads to chromosome segregation errors by allowing mitotic exit in the presence of unattached kinetochores (1). After several rounds of cell division, the accumulation of chromosome segregation errors results in cancer cell death by apoptosis (2). Several TTK inhibitors have been shown to reduce the growth of xenografts of human cancer cell lines from diverse tumor tissue origin in mice. In an immunocompetent mouse model of triple-negative breast cancer (TNBC), TTK inhibitors increased the efficacy of taxane chemotherapy (1). While the first TTK inhibitors have entered phase 1 dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. To enable the selection of patients most likely to respond to TTK inhibitor therapy, we profiled a set of ten preclinical and clinical inhibitors (3) on a panel of 66 genetically characterized cancer cell lines derived from different tumor tissues (Oncolines) (4). Drug sensitivity was related to the mutation status of 114 cancer genes in an unbiased way. Cell lines harboring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signaling regulator β-catenin, were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1. The association of CTNNB1 mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harboring either mutant or wild-type CTNNB1. Treatment of a xenograft model of a CTNNB1 mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in CTNNB1 occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high TTK levels (5). Interestingly, β-catenin signaling has also been implicated in intrinsic resistance against immunotherapy in melanoma by regulation of T cell infiltration (6). We propose mutant CTNNB1 as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials.