Pyrvinium Pamoate and BCL-XL Inhibitors Act Synergistically to Kill Patient-Derived Colorectal Adenoma Organoids

Faux, Maree C; Ma, Chenkai; Kane, Serena R; Samson, Andre; Hirokawa, Yumiko; Priebe, Ilka; Cosgrove, Leah; Singh, Rajvinder; Christie, Michael; Brown, Gregor; Fung, Kim YC; Burgess, Antony W

Author(s): Faux, Maree C; Ma, Chenkai; Kane, Serena R; Samson, Andre; Hirokawa, Yumiko; Priebe, Ilka; Cosgrove, Leah; Singh, Rajvinder; Christie, Michael; Brown, Gregor; Fung, Kim YC; Burgess, Antony W;
Details: Publication Year 2025,Volume 4,Issue #3,Page 15
Journal Title: Organoids
Abstract: Current systemic therapies for advanced colorectal cancer (CRC) have limited efficacy, so more effective strategies for the treatment and prevention of CRC are needed. The majority of colorectal cancers are initiated by mutations in Wnt signalling pathway genes, including mutations in the APC gene, which result in a truncated APC protein and lead to excess signalling from β-catenin and the formation of pre-cancerous adenomas. The aim of this study was to determine if targeting the Wnt pathway in combination with pro-apoptotic mimetics altered the proliferative capacity or viability of human colorectal adenoma cells. Patient-derived colorectal adenoma organoid cultures were established from colon adenoma tissue collected by colonoscopy and recapitulated the histopathology of primary colorectal adenoma tissue. The growth of colorectal adenoma organoids is inhibited by the Wnt-signalling antagonist pyrvinium pamoate (PP) and a pro-apoptotic inhibitor of BCL-XL but not BCL-2 (venetoclax) or MCL-1 inhibitors. At low concentrations, the PP and the BCL-XL inhibitor combination demonstrated potent synergy and induced apoptosis in APC-defective patient-derived adenoma organoids, even in the presence of oncogenic KRAS or BRAF mutations, providing a new strategy for colon cancer prevention.
Publisher: MDPI
Keywords: intestinal organoids; adenoma; adenomatous polyposis coli; colorectal cancer
Research Division(s): Personalised Oncology; Inflammation
Publisher's Version: https://doi.org/10.3390/organoids4030015
Open Access at Publisher's Site: https://doi.org/10.3390/organoids4030015
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-12-05 09:25:51

Last Modified: 2025-12-05 09:29:44