Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer

Gemcitabine remains a cornerstone of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) but acquired resistance limits its efficacy. While both microenvironment-derived metabolites and intrinsic metabolic reprogramming have been implicated in gemcitabine resistance, the relationship between these mechanisms remains poorly understood. We investigated the metabolic adaptations accompanying acquired gemcitabine resistance and identified therapeutically actionable vulnerabilities.

Acquired gemcitabine-resistant PDAC models were generated and characterized. The effects of physiological pyrimidines on gemcitabine response were evaluated alongside changes in pyrimidine metabolism. Sensitivity to inhibition of the mevalonate pathway was assessed in vitro and in immunocompetent mouse models. Metabolite rescue experiments were performed to identify critical downstream mediators of statin activity and HMGCR expression was analyzed for its association with clinical response to gemcitabine.

PDAC cells with acquired gemcitabine resistance exhibited diminished sensitivity to physiological extracellular pyrimidines due to suppression of the pyrimidine salvage pathway. This metabolic rewiring created a selective dependency on the mevalonate biosynthesis pathway, rendering gemcitabine resistant cells highly sensitive to statins. Statin treatment selectively inhibited the growth of gemcitabine-resistant tumors in mice. Metabolite rescue studies identified geranylgeranyl pyrophosphate depletion, not cholesterol limitation, as a principal mediator of statin sensitivity. HMGCR expression declined progressively during the acquisition of gemcitabine resistance and low HMGCR expression levels predicted poor response to gemcitabine-based therapy in PDAC patients.

Acquired gemcitabine resistance drives metabolic reprogramming that suppresses pyrimidine salvage while creating a therapeutically exploitable dependence on the mevalonate pathway. These findings identify pharmacological inhibition of HMGCR as a metabolic vulnerability in gemcitabine resistance and support HMGCR expression as a candidate biomarker for treatment stratification in PDAC patients.