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  • Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer.

Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer.

Cell reports. Medicine (2020-12-10)
Rawand Masoud, Gabriela Reyes-Castellanos, Sophie Lac, Julie Garcia, Samir Dou, Laetitia Shintu, Nadine Abdel Hadi, Tristan Gicquel, Abdessamad El Kaoutari, Binta Diémé, Fabrice Tranchida, Laurie Cormareche, Laurence Borge, Odile Gayet, Eddy Pasquier, Nelson Dusetti, Juan Iovanna, Alice Carrier
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

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Accutase® solution, sterile-filtered, suitable for cell culture
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