Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer

Area of Science:

• Biochemistry
• Oncology
• Metabolic pathways

Background:

• Mitochondrial respiration (oxidative phosphorylation, OXPHOS) is a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC).
• Significant patient-to-patient variability in metabolic adaptations within PDAC tumors remains uncharacterized.
• Understanding metabolic heterogeneity is crucial for developing effective PDAC treatments.

Purpose of the Study:

• To assess the heterogeneity of OXPHOS rates in PDAC patient tumors.
• To investigate the potential of targeting OXPHOS in combination with standard chemotherapy.
• To identify PDAC patient subpopulations likely to benefit from metabolic targeting.

Main Methods:

• Functional assessment of OXPHOS rates across patient-derived PDAC tumors.
• Analysis of mitochondrial respiratory complex I expression at protein and mRNA levels.
• In vitro and in vivo evaluation of phenformin (complex I inhibitor) combined with gemcitabine.

Main Results:

• OXPHOS rates demonstrated significant heterogeneity among PDAC tumors.
• High OXPHOS tumors exhibited enrichment of mitochondrial respiratory complex I.
• The combination of phenformin and gemcitabine showed synergistic efficacy specifically in high OXPHOS PDAC cells and tumors.
• Phenformin plus gemcitabine demonstrated cooperative effects in orthotopic mouse models.

Conclusions:

• A strategy is proposed to identify PDAC patients responsive to OXPHOS-targeted therapy.
• Phenformin in combination with gemcitabine shows promise for a subset of PDAC patients.
• Clinical trials of phenformin are warranted in identified PDAC patient subpopulations.