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

  • Oncotarget. 2016 Dec 6;7(49):81727-81740. doi: 10.18632/oncotarget.13172.
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
Affiliations
  • 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.
PMID: 27835580 DOI: 10.18632/oncotarget.13172
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 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.

Keywords
Apc mutation; K-Ras mutation; Ras destabilizer; metastatic colorectal cancer; tumor budding.
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