@article{08d390b72dcb4fa5b8dffee6be4444b9,
title = "Feasibility of targeting traf2-and-nck-interacting kinase in synovial sarcoma",
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.",
keywords = "MYC, NCB-0846, Synovial sarcoma, TNIK, Wnt signaling",
author = "Tetsuya Sekita and Tesshi Yamada and Eisuke Kobayashi and Akihiko Yoshida and Toru Hirozane and Akira Kawai and Yuko Uno and Hideki Moriyama and Masaaki Sawa and Yuichi Nagakawa and Akihiko Tsuchida and Morio Matsumoto and Masaya Nakamura and Robert Nakayama and Mari Masuda",
note = "Funding Information: Funding: This study was supported by the National Cancer Center Research and Development Fund (30-A-2 to M.M. (Mari Masuda)), the Acceleration Transformative Research for Medical Innovation (ACT-MS) program of the Japan Agency for Medical Research and Development (AMED) (16im0210804h0001 to T.Y.), the Kobayashi Foundation for Cancer Research (to T.Y.), a KAKENHI Grant-in-Aid for Challenging Research (16K14627 to M.M. (Mari Masuda) and 19H05566 to T.Y.), a Grant-in Aid for Scientific Research (B) (17H03603 to M.M. (Mari Masuda)) from the Japan Society for the Promotion of Science (JSPS), a Cancer Research Grant from the Foundation for Promotion of Cancer Research in Japan (to M.M. (Mari Masuda)), a Research Grant from the Princess Takamatsu Cancer Research Fund (to M.M. (Mari Masuda)), and a Grant-in-Aid for Early-Career Scientists (19J21415 to T.S.) of the Japan Society for the Promotion of Science (JSPS). Funding Information: Conflicts of Interest: U.Y., H.M., and M.S. are employees of Carna Biosciences, Inc. T.Y. and M.M. (Mari Masuda) have received a research grant from Carna Biosciences, Inc. The remaining authors have no conflicts of interest to declare. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = may,
doi = "10.3390/cancers12051258",
language = "English",
volume = "12",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "5",
}
