TNIK inhibition abrogates colorectal cancer stemness

  • Nat Commun. 2016 Aug 26;7:12586. doi: 10.1038/ncomms12586.
Mari Masuda  1 ,  Yuko Uno  2 ,  Naomi Ohbayashi  3 ,  Hirokazu Ohata  4 ,  Ayako Mimata  1 ,  Mutsuko Kukimoto-Niino  3 ,  Hideki Moriyama  2 ,  Shigeki Kashimoto  2 ,  Tomoko Inoue  2 ,  Naoko Goto  1 ,  Koji Okamoto  4 ,  Mikako Shirouzu  3 ,  Masaaki Sawa  2 ,  Tesshi Yamada  1
Affiliations
  • 1. Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  • 2. Carna Biosciences, Inc., BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
  • 3. Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
  • 4. Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
PMID: 27562646 DOI: 10.1038/ncomms12586
Abstract

Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and Others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik(-/-)/APC(min/+) mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in APC(min/+) mice and the sphere- and tumour-forming activities of colorectal Cancer cells. TNIK is required for the tumour-initiating function of colorectal Cancer Stem Cells. Its inhibition is a promising therapeutic approach.

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