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TNIK inhibition abrogates colorectal cancer stemness

Author

Listed:
  • Mari Masuda

    (National Cancer Center Research Institute)

  • Yuko Uno

    (Carna Biosciences, Inc.)

  • Naomi Ohbayashi

    (RIKEN Center for Life Science Technologies)

  • Hirokazu Ohata

    (National Cancer Center Research Institute)

  • Ayako Mimata

    (National Cancer Center Research Institute)

  • Mutsuko Kukimoto-Niino

    (RIKEN Center for Life Science Technologies)

  • Hideki Moriyama

    (Carna Biosciences, Inc.)

  • Shigeki Kashimoto

    (Carna Biosciences, Inc.)

  • Tomoko Inoue

    (Carna Biosciences, Inc.)

  • Naoko Goto

    (National Cancer Center Research Institute)

  • Koji Okamoto

    (National Cancer Center Research Institute)

  • Mikako Shirouzu

    (RIKEN Center for Life Science Technologies)

  • Masaaki Sawa

    (Carna Biosciences, Inc.)

  • Tesshi Yamada

    (National Cancer Center Research Institute)

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−/−/Apcmin/+ 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 Apcmin/+ 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.

Suggested Citation

  • Mari Masuda & Yuko Uno & Naomi Ohbayashi & Hirokazu Ohata & Ayako Mimata & Mutsuko Kukimoto-Niino & Hideki Moriyama & Shigeki Kashimoto & Tomoko Inoue & Naoko Goto & Koji Okamoto & Mikako Shirouzu & M, 2016. "TNIK inhibition abrogates colorectal cancer stemness," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12586
    DOI: 10.1038/ncomms12586
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