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

The lack of experimental systems that faithfully model the genetic and phenotypic progression from Barrett’s esophagus (BE) to gastroesophageal adenocarcinoma (GEAC) has limited mechanistic discovery and preclinical testing. 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. Together, these integrated in vivo and organoid platforms represent a technical advance for modelling BE progression, dissecting KRAS pathway biology, and evaluating targeted strategies for KRAS amplified GEAC.