Abstract
Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound metabolic plasticity and remains highly resistant to therapy. Activating KRAS mutations occur in approximately 90% of PDACs, with KRAS G12D being the most prevalent variant (~ 35–40%). Recent evidence indicates that KRAS G12D PDAC cells exploit KHK-C-dependent fructolysis, enabling fructose-derived carbon to bypass the phosphofructokinase-1 glycolytic checkpoint and sustain anabolic metabolism under nutrient stress. This metabolic dependency provides a potential therapeutic vulnerability, but the ability of PDAC cells to adapt to metabolic inhibition may limit the efficacy of single-target approaches.
Methods
We review the emerging role of fructose metabolism in KRAS-driven PDAC and discuss the therapeutic potential of targeting fructolysis using specific inhibitors of fructose uptake and metabolism, including AKR1B1, and KHK inhibitors. We further consider high-dose sodium citrate (SCT) as a complementary metabolic strategy to reinforce fructolysis inhibition and potentially constrain metabolic adaptation.
Results
Preclinical studies support KHK-C-dependent fructolysis as a metabolic vulnerability in KRAS G12D PDAC. However, the metabolic flexibility of PDAC cells raises the possibility that inhibition of a single fructolytic pathway may induce compensatory metabolic rewiring and limit therapeutic efficacy. SCT, through its broader effects on glycolytic and mitochondrial metabolism, may increase metabolic stress and tumor-cell vulnerability and thereby potentiate the effects of fructolysis inhibitors. Importantly, SCT also inhibits the growth of experimental PDAC models harboring KRAS G12D, KRAS G12C, KRAS G12V, and KRAS wild-type backgrounds, suggesting that its antitumor activity may extend beyond fructolytic KRAS G12D tumors. SCT may additionally enhance tumor-cell sensitivity to commonly used PDAC chemotherapeutics and cytotoxic immune responses.
Conclusions
Fructolysis represents an emerging metabolic vulnerability in KRAS G12D PDAC that may be therapeutically exploited using specific pathway inhibitors. Combining fructolysis inhibition with SCT may provide a broader metabolic strategy capable of limiting adaptive metabolic responses and enhancing tumor vulnerability. The activity of SCT across distinct KRAS backgrounds further suggests a potentially broader therapeutic role that warrants investigation independently of KRAS G12D-associated fructolytic dependency.