TNIK inhibition abrogates colorectal cancer stemness

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, Masaaki Sawa and Tesshi Yamada ()
Additional contact information
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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12586

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