Targeting Kras signalling in a Trp53/KrasG12D mouse and organoid model inhibits Barrett esophagus to gastroesophageal adenocarcinoma progression

Abstract 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: TP53 loss and elevated KRAS signalling driven by wildtype KRAS amplification, which we model in the L2-IL-1B mouse model by using oncogenic Kras G12D activation, since direct modelling of wildtype Kras amplification in vivo remains challenging. This combinatorial genetic approach accelerates malignant transformation and enables controlled, stage-resolved analysis of carcinogenesis at the gastroesophageal junction (GEJ). In parallel, murine Kras G12D driven and human KRAS wildtype amplified organoid systems recapitulate these in vivo phenotypes and provide a platform for functional interrogation of aberrant KRAS signalling, a frequent but understudied driver in GEAC. Using the human derived KRAS wildtype amplified organoids as treatment avatars in addition to the Kras G12D driven mouse model and its corresponding organoids, 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.