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 (Oncolines™ – see website www.oncolines.com)

  • 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.

NTRC 0066-0 volcano plot

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.

dose reponse curves for NTRC 0066-0 with isogenic cell lines

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.

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