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

초록

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/beta-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 beta-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 beta-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 beta-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells.

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