A team including scients at the National Cancer Center (NCC) (Tokyo, Japan), the RIKEN Center for Life Science Technologies (CLST) (Yokohama, Japan), and Carna Biosciences Inc. (Kobe, Japan) has jointly announced the development of a novel small-molecule Wnt inhibitor named NCB-0846. Wnt signaling is a key pathway of cancer stem cell (CSC) development. The inhibitor may provide a new therapy option for patients with drug-refractory colorectal cancer. Colorectal cancer is a major cause of cancer death, accounting for approximately 700,000 deaths annually worldwide. Over 90% of colorectal cancers carry somatic mutations in Wnt signaling component genes such as the adenomatous polyposis coli (APC) tumor suppressor gene, resulting in constitutive activation of Wnt signaling. This in turn leads to the generation of CSCs, which are intrinsically resistant to conventional chemotherapy. Therefore, therapeutics that can block Wnt signaling are likely to eradicate cancer stem cells and cure the disease. However, despite a wealth of data and investment in research and development, no Wnt-inhibiting drug has yet been incorporated into clinical practice. NCC researchers have previously examined the components of the T-cell factor-4 (TCF4) and β-catenin transcription complex and identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the TCF4/β-catenin complex. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its pharmacological inhibition has been anticipated to block the signal even in colorectal cancer cells with mutation of the APC gene.
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