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

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

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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