Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer
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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.
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The regulatory consequences of Sp/Klf motif enrichment are in genes associated with modulation of reactive oxygen species and metabolism such as SOD1, ID1, and NDUFV2.
“In doing so, we find that the regulatory consequences of Sp/Klf motif enrichment are in genes associated with modulation of reactive oxygen species and metabolism such as SOD144, ID145, and NDUFV246.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as [46]
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Self-citation
- Authors
- Masoud, R., Reyes-Castellanos, G., Lac, S., Garcia, J., Dou, S., Shintu, L., Abdel Hadi, N., Gicquel, T., El Kaoutari, A., Diémé, B., Tranchida, F., Cormareche, L., Borge, L., Gayet, O., Pasquier, E., Dusetti, N., Iovanna, J., & Carrier, A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Masoud, Rawand
- Carrier, Alice
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 1
- Issue
- 8
- Pages
- 100143
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC7691450
- OpenAlex
- W3101012847
- Cited by
- 175
- References
- 47
- Citations by year
- 2026: 14 · 2025: 35 · 2024: 49 · 2023: 27 · 2022: 27 · 2021: 23
- FWCI
- 6.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL AMU (submittedVersion, cc-by-nc-nd)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Fondation ARC pour la Recherche sur le Cancer (PJA 20151203544)
- La Ligue Nationale contre le Cancer
- DGOS
- Fondation Amidex
- Fondation de France
- Canceropôle Provence-Alpes-Côte d’Azur
- Fédération GEFLUC
- Fondation pour la Recherche Médicale
- CONACYT (339091/471717)
- IMODI
- Association Azm et Saadé
- Agence Nationale de la Recherche
- Canceropôle PACA
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- pancreatic ductal adenocarcinoma, mitochondrial complex I, oxidative phosphorylation, chemoresistance, phenformin, gemcitabine, combination chemotherapy, tumor metabolic heterogeneity, mitochondrial respiration, synergistic drug combination, patient stratification
- MeSH terms
- PC-3 Cells, Gemcitabine, Animals, Deoxycytidine, Female, Humans, Male, Mice, Inbred C57BL, Mice, Nude, Mitochondria, Oxidative Phosphorylation, Pancreatic Neoplasms, Phenformin, Drug Resistance, Neoplasm, Cell Respiration, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Electron Transport Complex I, Cell Line, Tumor, Cell Proliferation, Mice
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