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

Approximately 90% of patients with pancreatic cancer harbor KRAS mutations, predominantly the KRAS G12D subtype. HRS-4642, a non-covalent inhibitor targeting KRAS G12D , demonstrates potent antitumor efficacy but may ultimately lead to resistance. This study investigates the mechanisms underlying KRAS G12D inhibitor resistance and evaluates strategies to enhance treatment sensitivity. Our findings indicate that a glutamine-restricted diet not only reverses KRAS G12D inhibitor resistance in pancreatic ductal adenocarcinoma (PDAC) but also achieves remission with prolonging survival. Mechanistically, KRAS G12D 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 upregulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRAS G12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRAS G12D mutant PDAC.