Project Description

Patient stratification markers for TTK inhibitors

Analysis of drug response in relation to gene alterations

  • The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation.

  • A set of (pre)clinical TTK inhibitors from different chemical series were profiled on a panel of cancer cell lines from different tumors.

  • Cell lines harboring activating mutations in the CTNNB1 gene 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.

  • 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.

Link to the publication describing these findings (Zaman et al, 2017)

Relationship between cancer cell line sensitivity to TTK inhibitor NTRC 0066-0 and mutant status of 23 frequently mutated cancer genes, visualized in a volcano plot.

Representative dose-response curves of NTRC 0066-0 in proliferation assays with parental HCT 116 cells (ΔS45/+, in red) and an isogenic cell line lacking the mutated CTNNB1 gene copy (-/+, in green) or the wild-type gene copy (ΔS45/-, in blue).

xenograft model

Time course of tumor growth of the A427 xenograft model, homozygous CTNNB1-mutant lung carcinoma cell line.