Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer

Mitochondrial respiration (oxidative phosphorylation, OXPHOS) is an emerging target in currently refractory cancers such as pancreatic ductal adenocarcinoma (PDAC). However, the variability of energetic metabolic adaptations between PDAC patients has not been assessed in functional investigations. In this work, we demonstrate that OXPHOS rates are highly heterogeneous between patient tumors, and that high OXPHOS tumors are enriched in mitochondrial respiratory complex I at protein and mRNA levels. Therefore, we treated PDAC cells with phenformin (complex I inhibitor) in combination with standard chemotherapy (gemcitabine), showing that this treatment is synergistic specifically in high OXPHOS cells. Furthermore, phenformin cooperates with gemcitabine in high OXPHOS tumors in two orthotopic mouse models (xenografts and syngeneic allografts). In conclusion, this work proposes a strategy to identify PDAC patients likely to respond to the targeting of mitochondrial energetic metabolism in combination with chemotherapy, and that phenformin should be clinically tested in appropriate PDAC patient subpopulations. [Display omitted] Pancreatic ductal adenocarcinoma (PDAC) displays OXPHOS heterogeneityHigh OXPHOS PDAC tumors are enriched in mitochondrial respiratory complex IComplex I inhibitor phenformin synergizes with chemotherapy in high OXPHOS cellsPhenformin cooperates with gemcitabine antitumoral activity in high OXPHOS tumors Masoud et al. reveal that pancreatic cancer patients can be stratified according to their mitochondrial oxidative phosphorylation (OXPHOS) activity and to the expression of mitochondrial respiratory complex I. Targeting mitochondrial respiration with the complex I inhibitor phenformin cooperates with gemcitabine to eradicate high OXPHOS pancreatic cancer cells.