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

// Yong-Hee Cho 1, 2 , Pu-Hyeon Cha 1, 2 , Saluja Kaduwal 1, 2 , Jong-Chan Park 1, 2 , Sang-Kyu Lee 1, 2 , Jeong-Soo Yoon 1, 2 , Wookjin Shin 1, 2 , Hyuntae Kim 1, 2 , Eun Ji Ro 1, 2 , Kyung-Hwa Koo 1, 2 , Ki-Sook Park 3 , Gyoonhee Han 1, 2 , Kang-Yell Choi 1, 2 1 Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea 3 College of Medicine, East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Korea Correspondence to: Kang-Yell Choi, email: kychoi@yonsei.ac.kr Keywords: Apc mutation, K-Ras mutation, tumor budding, metastatic colorectal cancer, Ras destabilizer Received: August 20, 2016      Accepted: October 19, 2016      Published: November 07, 2016 ABSTRACT 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 APC Min /+ /K-Ras G12D LA2 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.