Feasibility of targeting traf2-and-nck-interacting kinase in synovial sarcoma

Tetsuya Sekita, Tesshi Yamada, Eisuke Kobayashi, Akihiko Yoshida, Toru Hirozane, Akira Kawai, Yuko Uno, Hideki Moriyama, Masaaki Sawa, Yuichi Nagakawa, Akihiko Tsuchida, Morio Matsumoto, Masaya Nakamura, Robert Nakayama, Mari Masuda

Research output: Contribution to journalArticle

Abstract

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 TNIK 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 TNIK for proliferation and survival. NCB-0846 induced apoptotic cell death in synovial sarcoma cells through blocking of Wnt target genes including MYC, 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.

Original languageEnglish
Article number1258
JournalCancers
Volume12
Issue number5
DOIs
Publication statusPublished - 2020 May

Keywords

  • MYC
  • NCB-0846
  • Synovial sarcoma
  • TNIK
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Sekita, T., Yamada, T., Kobayashi, E., Yoshida, A., Hirozane, T., Kawai, A., Uno, Y., Moriyama, H., Sawa, M., Nagakawa, Y., Tsuchida, A., Matsumoto, M., Nakamura, M., Nakayama, R., & Masuda, M. (2020). Feasibility of targeting traf2-and-nck-interacting kinase in synovial sarcoma. Cancers, 12(5), [1258]. https://doi.org/10.3390/cancers12051258