Small molecule-induced simultaneous destabilization of β-catenin and RAS is an effective molecular strategy to suppress stemness of colorectal cancer cells

Yong Hee Cho, Eun Ji Ro, Jeong Su Yoon, Dong Kyu Kwak, Jaebeom Cho, Dong Woo Kang, Ho Young Lee, Kang Yell Choi

Research output: Contribution to journalArticle

Abstract

Background: Cancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood. Methods: Gene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set. The therapeutic effects of destabilization of β-catenin and RAS were tested by treatment of small molecule KYA1797K using CRC patient derived cells. Results: Treatment with KYA1797K, a small molecule that destabilizes both β-catenin and RAS via Axin binding, effectively suppresses the stemness of CSCs as shown in CRC spheroids and small intestinal tumors of Apc Min/+/K-Ras G12D LA2 mice. Moreover, KYA1797K also suppresses the stemness of cells in CRC patient avatar model systems, such as patient-derived tumor organoids (PDTOs) and patient-derived tumor xenograft (PDTX). Conclusion: Our results suggest that destabilization of both β-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells. [MediaObject not available: see fulltext.]

Original languageEnglish
Article number38
JournalCell Communication and Signaling
Volume18
Issue number1
DOIs
Publication statusPublished - 2020 Mar 6

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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