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 .

中文翻译：

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TTK抑制剂作为CTNNB1（{beta} -catenin）突变癌症的靶向治疗。

纺锤体装配检查点激酶TTK（Mps1）是染色体分离的关键调节剂，是小分子抑制剂的新型靶向治疗方法的主题。尽管首批TTK抑制剂已与紫杉烷类化学疗法一起进入I期剂量递增研究，但仍缺乏患者分层策略。为了识别基因组生物标记物以预测肿瘤细胞对TTK抑制剂治疗的反应，我们在来自不同肿瘤（Oncolines）的66种具有遗传特征的细胞系的面板上，对一组来自不同化学系列的临床前和临床TTK抑制剂进行了分析。 。在CTNNB1基因中包含活化突变的细胞系，编码Wnt信号通路调控因子β-catenin，对TTK抑制剂的敏感性平均要比野生型CTNNB1细胞高五倍。携带突变型或野生型CTNNB1的同基因细胞系对证实了CTNNB1突变状态与癌细胞株对TTK抑制敏感性增加的关联。用TTK抑制剂NTRC 0066-0处理CTNNB1突变细胞系的异种移植模型导致肿瘤生长的完全抑制。CTNNB1的突变在子宫内膜癌和肝细胞癌中以较高的频率发生，已知它们表达高的TTK水平。我们建议将突变体CTNNB1作为预后药物反应的生物标志物，从而能够在概念验证的临床试验中选择最可能对TTK抑制剂疗法产生反应的患者。分子癌疗法；16（11）; 2609–17。©2017 AACR。携带突变型或野生型CTNNB1的同基因细胞系对证实了CTNNB1突变状态与癌细胞株对TTK抑制敏感性增加的关联。用TTK抑制剂NTRC 0066-0处理CTNNB1突变细胞系的异种移植模型导致肿瘤生长的完全抑制。CTNNB1的突变在子宫内膜癌和肝细胞癌中以较高的频率发生，已知它们表达高的TTK水平。我们建议将突变体CTNNB1作为预后药物反应的生物标志物，从而能够在概念验证的临床试验中选择最可能对TTK抑制剂疗法产生反应的患者。分子癌疗法；16（11）; 2609–17。©2017 AACR。携带突变型或野生型CTNNB1的同基因细胞系对证实了CTNNB1突变状态与癌细胞株对TTK抑制敏感性增加的关联。用TTK抑制剂NTRC 0066-0处理CTNNB1突变细胞系的异种移植模型导致肿瘤生长的完全抑制。CTNNB1的突变在子宫内膜癌和肝细胞癌中以较高的频率发生，已知它们表达高的TTK水平。我们建议将突变体CTNNB1作为预后药物反应的生物标志物，从而能够在概念验证的临床试验中选择最可能对TTK抑制剂疗法产生反应的患者。分子癌疗法；16（11）; 2609–17。©2017 AACR。