title: Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer.
abstract: The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of the most notable findings is that the great majority of colorectal cancers (>80%) have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Loss of functional APC protein results in activation of canonical Wnt/β-catanin signaling and initiates intestinal carcinogenesis. Mutational inactivation of APC is the first genetic event, but colorectal cancer cells retain their dependency on constitutive Wnt signal activation even after accumulation of other genetic events. Accordingly, pharmacological blocking of Wnt signaling has been considered an attractive therapeutic approach for colorectal cancer. Several therapeutics targeting various molecular components of the Wnt signaling pathway, including porcupine, frizzled receptors and co-receptor, tankyrases, and cAMP response element binding protein (CREB)-binding protein (CBP), have been developed, and some of those are currently being evaluated in early-phase clinical trials. Traf2- and Nck-interacting protein kinase (TNIK) has been identified as a regulatory component of the T-cell factor-4 and β-catenin transcriptional complex independently by two research groups. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its inhibition is expected to block the signal even in colorectal cancer cells with APC gene mutation. Here we discuss some of the TNIK inhibitors under preclinical development.
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Masuda
authors.affiliation: Carna Biosciences, Inc., Kobe 650-0047, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sawa
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan. Electronic address: tyamada@ncc.go.jp.
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000503:physiopathology*; D017491:Genes, APC / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D047908:Intracellular Signaling Peptides and Proteins; D047992:TNF Receptor-Associated Factor 2; D051153:Wnt Proteins; D051176:beta Catenin; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Cancer stem cell; Colorectal cancer; Molecular targeting therapy; Traf2- and Nck-interacting kinase (TNIK); Wnt signaling