DS-2087b誘発胃腸毒性におけるマウスおよびサル腸管オルガノイドを用いた種間差の評価

Gastrointestinal (GI) toxicity is a common adverse event induced by anti-cancer drugs; however, the information of the correlations in vitro to in vivo regarding GI toxicity is limited. The objective of this study was elucidating the usefulness of animal small intestinal organoids using DS-2087b, a novel epidermal growth factor receptor/human epidermal growth factor receptor 2 exon 20 insertion inhibitor. Mice showed no DS-2087b-related GI toxicities up to 100 mg/kg in 28-day repeated oral toxicity studies, while monkeys exhibited diarrhea at 10 mg/kg, along with histopathological changes including intestinal atrophy/erosion at 30 and 100 mg/kg. To clarify the mechanisms involved in interspecies differences, cell viability and transcriptomic analysis were performed using mouse and monkey small intestinal organoids generated from adult stem cells treated with DS-2087b at 0-10,000 nM for 3 days. Cell viability in monkey small intestinal organoids treated with DS-2087b at 1000 and 10,000 nM was significantly decreased compared to that of mice. In the transcriptomic analysis, expression of stem- and Paneth-cell marker genes was markedly decreased in the monkey small intestinal organoids. In conclusion, the intestinal organoids are valuable in vivo-in vitro translation of drug-induced GI toxicity and the changes in specific cell-type composition induced by DS-2087b may be important factors for contributing the interspecies differences.