BACKGROUND:NAD(P)H quinone dehydrogenase 1 (NQO1), a detoxification enzyme regulated by the Nrf2 cytoprotective pathway, is overexpressed in pancreatic ductal adenocarcinoma (PDAC). NQO1 levels are also influenced by the C609T single-nucleotide polymorphism (SNP). We hypothesized that elevated NQO1 would confer chemoresistance in PDAC and predict poor patient outcome. METHODS:NQO1 tumor levels and germline C609T SNP status were assessed in archival samples from the European Study Group for Pancreatic Cancer (ESPAC) trials. NQO1 expression (H-score) was treated as continuous for survival regression analyses and dichotomized for visual summaries. Nrf2 or downstream gene induction was assessed in Nrf2 reporter mice or in PDAC cells following exposure to gemcitabine (Gem), 5-fluorouracil (5-FU), or the capecitabine (Cap) metabolite 5-fluoro-5'-deoxyuridine (5'-DFUR). Colony formation following NQO1 depletion was assessed. RESULTS:NQO1 tumor levels correlated with germline C609T SNP status (P < .001). Contrary to our hypothesis, high NQO1 expression was associated with improved survival in ESPAC-4 patients randomized to GemCap (HR = 0.87 [95% CI = 0.751 to 0.999]; P = .049), and had no association to outcome in the Gem-only treated arm (HR = 0.98 [95% CI = 0.78 to 1.23]; P = .867). Including genotype data did not improve predictive model performance. Neither Gem nor 5-FU induced Nrf2 in vivo. At high concentrations, they suppressed Nrf2/NQO1 in PDAC cells, an effect not mitigated by co-treatment with 5'-DFUR. NQO1 depletion experiments revealed that NQO1 inhibits colony formation. The strongest inhibition was observed when NQO1-positive cells were co-treated with Gem and 5'-DFUR, supporting our clinical data from ESPAC. CONCLUSION:High tumor NQO1 predicts better outcome following GemCap therapy.
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