Nature Communications (Feb 2025)
PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma
- Valentin Van den bossche,
- Julie Vignau,
- Engy Vigneron,
- Isabella Rizzi,
- Hannah Zaryouh,
- An Wouters,
- Jérôme Ambroise,
- Steven Van Laere,
- Simon Beyaert,
- Raphaël Helaers,
- Cédric van Marcke,
- Lionel Mignion,
- Elise Y. Lepicard,
- Bénédicte F. Jordan,
- Céline Guilbaud,
- Olivier Lowyck,
- Hajar Dahou,
- Antonella Mendola,
- Manon Desgres,
- Léo Aubert,
- Isabelle Gerin,
- Guido T. Bommer,
- Romain Boidot,
- Perrine Vermonden,
- Aurélien Warnant,
- Yvan Larondelle,
- Jean-Pascal Machiels,
- Olivier Feron,
- Sandra Schmitz,
- Cyril Corbet
Affiliations
- Valentin Van den bossche
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Julie Vignau
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Engy Vigneron
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Isabella Rizzi
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Hannah Zaryouh
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp
- An Wouters
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp
- Jérôme Ambroise
- Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Steven Van Laere
- Translational Cancer Research Unit (TCRU), GZA Ziekenhuizen
- Simon Beyaert
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
- Raphaël Helaers
- Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain
- Cédric van Marcke
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
- Lionel Mignion
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain
- Elise Y. Lepicard
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain
- Bénédicte F. Jordan
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain
- Céline Guilbaud
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Olivier Lowyck
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
- Hajar Dahou
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Antonella Mendola
- Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Manon Desgres
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Léo Aubert
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Isabelle Gerin
- Metabolic Research Group, de Duve Institute, UCLouvain
- Guido T. Bommer
- Metabolic Research Group, de Duve Institute, UCLouvain
- Romain Boidot
- Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges‑François Leclerc Cancer Center‑UNICANCER
- Perrine Vermonden
- Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain
- Aurélien Warnant
- Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain
- Yvan Larondelle
- Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain
- Jean-Pascal Machiels
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
- Olivier Feron
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- Sandra Schmitz
- King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
- Cyril Corbet
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
- DOI
- https://doi.org/10.1038/s41467-025-56675-3
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 21
Abstract
Abstract Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice. Importantly, the PPARα-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. This study points out lipid metabolism rewiring as a non-genetic resistance-causing mechanism in HNSCC that may be therapeutically targeted to overcome acquired resistance to anti-EGFR therapy.
