TNIK inhibition abrogates colorectal cancer stemness.

Mari Masuda,Tesshi Yamada,Yuko Uno,Shigeki Kashimoto,Mutsuko Kukimoto-Niino,Tomoko Inoue,Masaaki Sawa,Hideki Moriyama,Koji Okamoto,Naoko Goto,Mikako Shirouzu,Naomi Ohbayashi,Ayako Mimata,Hirokazu Ohata

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−/−/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.

Highlights

Canonical Wnt/b-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis
Wnt signalling is essential for maintaining the undifferentiated status and self-renewal capability of intestinal stem cells[6], and constitutive activation of Wnt signalling due to such genetic alterations most likely gives rise to tumour-initiating or cancer stem cells (CSCs)[7,8,9]
Traf2- and Nck-interacting kinase (TNIK) was essential for full activation of Wnt signalling, and colorectal cancer cells were highly dependent on TNIK for growth[17]

Summary

Introduction

Canonical Wnt/b-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/ þ mice and the sphere- and tumour-forming activities of colorectal cancer cells. Wnt signalling is essential for maintaining the undifferentiated status and self-renewal capability of intestinal stem cells[6], and constitutive activation of Wnt signalling due to such genetic alterations most likely gives rise to tumour-initiating or cancer stem cells (CSCs)[7,8,9]. TNIK was essential for full activation of Wnt signalling, and colorectal cancer cells were highly dependent on TNIK for growth[17]. We report the development of a novel small-molecule TNIK inhibitor having anti-Wnt and anti-cancer stem cell activities. We initiated this study by developing Tnik-deficient mice to confirm the safety and feasibility of TNIK targeting

Methods

Results

Conclusion