KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer

• Published in: Oncotarget 2016-12, Vol.7 (49), p.81727-81740
• Main Authors: Cho, Yong-Hee, Cha, Pu-Hyeon, Kaduwal, Saluja, Park, Jong-Chan, Lee, Sang-Kyu, Yoon, Jeong-Soo, Shin, Wookjin, Kim, Hyuntae, Ro, Eun Ji, Koo, Kyung-Hwa, Park, Ki-Sook, Han, Gyoonhee, Choi, Kang-Yell
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - drug effects; Actin Cytoskeleton - metabolism; Actin Cytoskeleton - pathology; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - secondary; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; beta Catenin - genetics; beta Catenin - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Models, Animal; Epithelial-Mesenchymal Transition - drug effects; Genes, APC; HEK293 Cells; Humans; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neoplasm Invasiveness; Protein Stability; Proteolysis; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Research Paper; Thiohydantoins - pharmacology; Time Factors; Wnt Signaling Pathway - drug effects
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.13172

APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.