突变体
癌症研究
Wnt信号通路
癌症
调节器
靶向治疗
细胞培养
医学
内科学
生物
基因
遗传学
作者
Guido J.R. Zaman,Jeroen A.D.M. de Roos,Marion A.A. Libouban,Martine B.W. Prinsen,Jos de Man,Rogier C. Buijsman,Joost C.M. Uitdehaag
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2017-11-01
卷期号:16 (11): 2609-2617
被引量:36
标识
DOI:10.1158/1535-7163.mct-17-0342
摘要
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 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. 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. Mol Cancer Ther; 16(11); 2609–17. ©2017 AACR.
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