TTK Inhibitors as a Targeted Therapy for <i>CTNNB1</i> ( <b>β</b> -catenin) Mutant Cancers

Abstract

The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the <i>CTNNB1</i> 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 <i>CTNNB1</i> The association of <i>CTNNB1</i>-mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harboring either mutant or wild-type <i>CTNNB1</i> Treatment of a xenograft model of a <i>CTNNB1</i>-mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in <i>CTNNB1</i> occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high <i>TTK</i> levels. We propose mutant <i>CTNNB1</i> 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. <i>Mol Cancer Ther; 16(11); 2609-17. ©2017 AACR</i>.