Glutamine-restricted diets restore sensitivity to KRAS^G12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming.

Abstract

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.