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 and Cyril Corbet ()
Additional contact information
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: GZA Ziekenhuizen
Simon Beyaert: King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
Raphaël Helaers: UCLouvain
Cédric van Marcke: King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
Lionel Mignion: UCLouvain
Elise Y. Lepicard: UCLouvain
Bénédicte F. Jordan: 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: UCLouvain
Guido T. Bommer: UCLouvain
Romain Boidot: 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

Nature Communications, 2025, vol. 16, issue 1, 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.

Date: 2025
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DOI: 10.1038/s41467-025-56675-3

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