Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells

• DOI: 10.1038/s41419-017-0199-9
• Publication Date: 2018-02-15T08:09:33Z
• Authors: Alistair J. Langl...; Thomas D. Carroll; Yu Chen; Inke Näthke
• Keywords: Wild type; Organoid

Abstract More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes stimulate optimal, but not excessive Wnt signalling, resulting a growth advantage mutant over wild-type cells. Reversal this constitutes potential therapeutic approach. We utilised intestinal organoids to compare the and Organoids derived from Min/+ mice recapitulate stages polyposis culture. They eventually form spherical cysts reflect competitive cells have undergone loss heterozygosity (LOH). discovered emergence was inhibited by Chiron99021 Valproic acid, which potentiates signalling. acid restrict while stimulating cells, suggesting reduces relative fitness As proof concept, we demonstrated Chiron99021-treated were rendered susceptible TSA-induced apoptosis, protected.