title: Targeting the Wnt signaling pathway in colorectal cancer.
abstract: BACKGROUND
  The treatment of patients with advanced colorectal cancer still remains challenging, and identification of new target molecules and therapeutic avenues remains a priority. The great majority of colorectal cancers have mutations in one of two genes involved in the Wnt signaling pathway: the adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes. Up to now, however, no therapeutics for targeting this pathway have been established.
  
  
  METHODS
  This review article begins with a brief summary of Wnt signaling from the viewpoints of genetics, cancer stem cell biology, and drug development. We then overview current attempts to develop drugs directed at various components of the Wnt signaling pathway.
  
  
  CONCLUSIONS
  APC is a tumor suppressor, and therefore only downstream signal transducers of the APC protein can be considered as targets for pharmaceutical intervention. TRAF2 and NCK-interacting protein kinase (TNIK) was identified as the most downstream regulator of Wnt signaling by two independent research groups, and several classes of small-molecule inhibitors targeting this protein kinase have been developed. TNIK is a multifunctional protein with actions that extend beyond Wnt signaling regulation. Such TNIK inhibitors are expected to have a large variety of clinical applications.
authors.affiliation: a 1 Carna Biosciences, Inc. , BMA 3F 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sawa
authors.affiliation: b 2 National Cancer Center Research Institute, Division of Chemotherapy and Clinical Research , 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Masuda
authors.affiliation: c 3 National Cancer Center Research Institute, Division of Chemotherapy and Clinical Research , 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan ; tyamada@ncc.go.jp.
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015195:Drug Design; D000081410:Germinal Center Kinases; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000081410:Germinal Center Kinases; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human
keywords: T-cell factor-4; TRAF2 and NCK-interacting protein kinase; Wnt signaling; cancer stem cell; colorectal cancer