Emergence of TNIK inhibitors in cancer therapeutics

Abstract

The outcome of patients with metastatic colorectal cancer remains unsatisfactory. To improve patient prognosis, it will be necessary to identify new drug targets based on molecules that are essential for colorectal carcinogenesis, and to develop therapeutics that target such molecules. The great majority of colorectal cancers (>90%) have mutations in at least one Wnt signaling pathway gene. Aberrant activation of Wnt signaling is a major force driving colorectal carcinogenesis. Several therapeutics targeting Wnt pathway molecules, including porcupine, frizzled receptors and tankyrases, have been developed, but none of them have yet been incorporated into clinical practice. Wnt signaling is most frequently activated by loss of function of the adenomatous polyposis coli (APC) tumor suppressor gene. Restoration of APC gene function does not seem to be a realistic therapeutic approach, and, therefore, only Wnt signaling molecules downstream of the APC gene product can be considered as targets for pharmacological intervention. Traf2 and Nck-interacting protein kinase (TNIK) was identified as a regulatory component of the β-catenin and T-cell factor-4 (TCF-4) transcriptional complex. Several small-molecule compounds targeting this protein kinase have been shown to have anti-tumor effects against various cancers. An anthelmintic agent, mebendazole, was recently identified as a selective inhibitor of TNIK and is under clinical evaluation. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its pharmacological inhibition seems to be a promising therapeutic approach. We demonstrated the feasibility of this approach by developing a small-molecule TNIK inhibitor, NCB-0846.

Keywords: TNIK; Cancer stem cell; Wnt signaling; colorectal cancer; molecular targeted therapy.

Figure 1

Frequent canonical Wnt/β‐catenin signaling pathway gene mutation in colorectal cancer. More than 80% of colorectal cancers have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Recent large‐scale sequencing efforts by the Cancer Genome Atlas and others have revealed frequent (over 90%) genetic alterations in Wnt signaling molecules.

Figure 2

Domain structure of TNIK (modified from Shitashige et al., 2010). CNH, citron homology.

Figure 3

TNIK is essential for colorectal cancer growth. Knockdown of TNIK by small hairpin RNA (shRNA) (TNIK 1, 2 and 3) and small interfering RNA (siRNA) (TNIK 12 and 13) inhibits the growth of colorectal cancer cells (TOP) and xenografts (BOTTOM), respectively (modified from Shitashige et al., 2010).

Figure 4

The effect of NCB‐0846 on Wnt‐driven tumorigenesis in Apc ^min/+ mice. Oral administration of NCB‐0846 was started at the age of 10 weeks. The mice were scarified 5 weeks later, and the number of tumors developed in the small intestine was counted (modified from Masuda et al., 2016). VEH, vehicle.