| First Author | Masuda M | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 12586 | PubMed ID | 27562646 |
| Mgi Jnum | J:241611 | Mgi Id | MGI:5903180 |
| Doi | 10.1038/ncomms12586 | Citation | Masuda M, et al. (2016) TNIK inhibition abrogates colorectal cancer stemness. Nat Commun 7:12586 |
| abstractText | Canonical Wnt/beta-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 beta-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. |
