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

Yong Hee Cho, Pu Hyeon Cha, Saluja Kaduwal, Jong Chan Park, Sang Kyu Lee, Jeong Soo Yoon, Wookjin Shin, Hyuntae Kim, Eun Ji Ro, Kyung Hwa Koo, Ki Sook Park, Gyoonhee Han, Kang Yell Choi

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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.

Original languageEnglish
Pages (from-to)81727-81740
Number of pages14
JournalOncotarget
Volume7
Issue number49
DOIs
Publication statusPublished - 2016 Jan 1

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All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Cho, Y. H., Cha, P. H., Kaduwal, S., Park, J. C., Lee, S. K., Yoon, J. S., Shin, W., Kim, H., Ro, E. J., Koo, K. H., Park, K. S., Han, G., & Choi, K. Y. (2016). KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer. Oncotarget, 7(49), 81727-81740. https://doi.org/10.18632/oncotarget.13172