靶向滑膜肉瘤中Traf2与Nck相互作用激酶的可行性
Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma.
作者信息
Sekita Tetsuya, Yamada Tesshi, Kobayashi Eisuke, Yoshida Akihiko, Hirozane Toru, Kawai Akira, Uno Yuko, Moriyama Hideki, Sawa Masaaki, Nagakawa Yuichi, Tsuchida Akihiko, Matsumoto Morio, Nakamura Masaya, Nakayama Robert, Masuda Mari
机构信息
Laboratory of Collaborative Research, Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
出版信息
Cancers (Basel). 2020 May 16;12(5):1258. doi: 10.3390/cancers12051258.
BACKGROUND
The treatment of patients with metastatic synovial sarcoma is still challenging, and the development of new molecular therapeutics is desirable. Dysregulation of Wnt signaling has been implicated in synovial sarcoma. Traf2-and-Nck-interacting kinase (TNIK) is an essential transcriptional co-regulator of Wnt target genes. We examined the efficacy of a small interfering RNA (siRNA) to and a small-molecule TNIK inhibitor, NCB-0846, for synovial sarcoma.
METHODS
The expression of TNIK was determined in 20 clinical samples of synovial sarcoma. The efficacy of NCB-0846 was evaluated in four synovial sarcoma cell lines and a mouse xenograft model.
RESULTS
We found that synovial sarcoma cell lines with Wnt activation were highly dependent upon the expression of for proliferation and survival. NCB-0846 induced apoptotic cell death in synovial sarcoma cells through blocking of Wnt target genes including , and oral administration of NCB-846 induced regression of xenografts established by inoculation of synovial sarcoma cells.
DISCUSSION
It has become evident that activation of Wnt signaling is causatively involved in the pathogenesis of synovial sarcoma, but no molecular therapeutics targeting the pathway have been approved. This study revealed for the first time the therapeutic potential of TNIK inhibition in synovial sarcoma.
背景
转移性滑膜肉瘤患者的治疗仍然具有挑战性，因此需要开发新的分子疗法。Wnt信号通路失调与滑膜肉瘤有关。肿瘤坏死因子受体相关因子2和Nck相互作用激酶（TNIK）是Wnt靶基因的重要转录共调节因子。我们研究了针对TNIK的小分子干扰RNA（siRNA）和小分子TNIK抑制剂NCB-0846对滑膜肉瘤的疗效。
方法
在20例滑膜肉瘤临床样本中检测TNIK的表达。在四种滑膜肉瘤细胞系和小鼠异种移植模型中评估NCB-0846的疗效。
结果
我们发现Wnt激活的滑膜肉瘤细胞系高度依赖TNIK的表达来进行增殖和存活。NCB-0846通过阻断包括AXIN2在内的Wnt靶基因，诱导滑膜肉瘤细胞发生凋亡性细胞死亡，口服NCB-846可使接种滑膜肉瘤细胞建立的异种移植瘤消退。
讨论
Wnt信号通路的激活在滑膜肉瘤发病机制中具有因果关系，这一点已变得很明显，但尚无针对该通路的分子疗法获得批准。本研究首次揭示了抑制TNIK在滑膜肉瘤中的治疗潜力。
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