Wnt信号通路
大肠腺瘤性息肉病
癌症研究
结直肠癌
连环素
生物
信号转导
连环蛋白
酪氨酸激酶
癌症
大肠癌小鼠模型的建立
细胞生物学
遗传学
作者
Laëtitia Ganier,S. Betzi,Carine Derviaux,Philippe Roche,Charlotte Dessaux,Christophe Müller,Laurent Hoffer,Xavier Morelli,Jean‐Paul Borg
标识
DOI:10.1021/acschembio.1c00826
摘要
Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/β-catenin pathway signaling, in part, through a kinase domain-dependent interaction with the β-catenin protein. PTK7 is overexpressed in CRC, an event associated with metastatic development and reduced survival of nonmetastatic patients. In addition, numerous alterations have been identified in CRC inducing constitutive activation of the Wnt/β-catenin pathway signaling through β-catenin accumulation. Thus, targeting the PTK7/β-catenin interaction could be of interest for future drug development. We have developed a NanoBRET screening assay recapitulating the interaction between PTK7 and β-catenin to identify compounds able to disrupt this protein–protein interaction. A high-throughput screening allowed us to identify small-molecule inhibitors targeting the Wnt pathway signaling and inducing antiproliferative and antitumor effects in vitro in CRC cells harboring β-catenin or adenomatous polyposis coli (APC) mutations. Thus, inhibition of the PTK7/β-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on the Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.
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