Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1-mediated metabolic reprogramming

ABSTRACT: This study investigates the mechanisms underlying KRASG12D inhibitor resistance and evaluates strategies to enhance treatment sensitivity. Our findings indicate that a glutamine-restricted diet not only reverses KRASG12D inhibitor resistance in PDAC but also achieves durable remission with long-term survival. Mechanistically, KRASG12D inhibitor resistance markedly upregulates ANXA1 expression, which, in turn, promotes its binding to the glutamine-related enzyme GOT1 and stabilizes its expression. Additionally, we find that ANXA1 up-regulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRASG12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRASG12D-mutant pancreatic ductal adenocarcinoma.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

PROVIDER: MTBLS14825 | MetaboLights | 2026-06-27

REPOSITORIES: MetaboLights