Prophylactic inhibition of LATS1/2 prior to high-dose irradiation promotes the regeneration of the damaged intestinal epithelium through Yap-dependent and independent mechanisms

Intestinal epithelial cells can respond to ionizing radiation (IR) injury through Yap-driven regenerative pathways that facilitate the regeneration and repopulation of the intestinal epithelium. Yap is a key effector of the Hippo signaling pathway but the impact of pharmacologic approaches manipulating Yap activity as a means of promoting intestinal IR response have not been thoroughly evaluated. This study evaluated a selective and potent small-molecule inhibitor of Yap’s upstream negative regulators LATS1 and LATS2 (LATS1/2) on small intestinal radiation response in vitro and in vivo. Transient administration of this compound prior to IR facilitated in vitro radioprotection using mouse-derived enteroids as well as an in vivo radioprotective effect when systemically administered to mice prior to doses of IR that normally result in gastrointestinal acute radiation syndrome (GI-ARS). Transient systemic treatment with NCGC-023 before IR decreased DNA-damage, pre-mitotic apoptosis, and aberrant mitosis in the crypt epithelium. Mechanistically, Lats1/2 inhibition with NCGC-023 prompted gene expression changes characteristic of both Yap-dependent regenerative responses and Yap-independent metallothionine stress responses.