Targeting KRAS in a TRP53/KRAS mouse and organoid model inhibits Barrett Esophagus to Gastroesophageal Adenocarcinoma progression

Here, we report a refined L2-IL-1B based mouse model engineered to capture two hallmark alterations of human GEAC: Trp53 loss and elevated KRAS signalling driven by KRAS amplification, modelled through oncogenic KrasG12D activation.

This combinatorial genetic approach accelerates malignant transformation and enables controlled, stage-resolved analysis of carcinogenesis at the gastroesophageal junction (GEJ). Parallel murine and human organoid systems recapitulate these in vivo phenotypes and provide a platform for functional interrogation of KRAS amplification, a frequent but understudied driver in GEAC. Using these organoids as treatment avatars in addition to the mouse model, we demonstrate that KRAS dependent growth is selectively vulnerable to combined SHP2 + MEK1/2 or ERK1/2 inhibition, revealing a therapeutically targetable signalling axis.