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

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/?-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 ?-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 ?-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^G12DLA2 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 ?-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells. Video abstract.

SUBMITTER: Cho YH 

PROVIDER: S-EPMC7060567 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature