2. Academic Validation
  3. PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma

PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma

  • Nat Commun. 2025 Feb 1;16(1):1237. doi: 10.1038/s41467-025-56675-3.
Valentin Van den Bossche # 1 2,  Julie Vignau # 1,  Engy Vigneron # 1,  Isabella Rizzi 1,  Hannah Zaryouh 3,  An Wouters 3,  Jérôme Ambroise 4,  Steven Van Laere 5,  Simon Beyaert 2 6 7,  Raphaël Helaers 8,  Cédric van Marcke 2 6,  Lionel Mignion 9,  Elise Y Lepicard 9,  Bénédicte F Jordan 9,  Céline Guilbaud 1,  Olivier Lowyck 2 6,  Hajar Dahou 6,  Antonella Mendola 6,  Manon Desgres 1,  Léo Aubert 1,  Isabelle Gerin 10,  Guido T Bommer 10,  Romain Boidot 11 12,  Perrine Vermonden 13,  Aurélien Warnant 13,  Yvan Larondelle 13,  Jean-Pascal Machiels 2 6 7,  Olivier Feron 1 14,  Sandra Schmitz 2 6 7,  Cyril Corbet 15 16
Affiliations

Affiliations

  • 1 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium.
  • 2 King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium.
  • 3 Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
  • 4 Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 54, B-1200, Brussels, Belgium.
  • 5 Translational Cancer Research Unit (TCRU), GZA Ziekenhuizen, Antwerp, Belgium.
  • 6 Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B-1200, Brussels, Belgium.
  • 7 Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium.
  • 8 Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, B-1200, Brussels, Belgium.
  • 9 Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, B-1200, Brussels, Belgium.
  • 10 Metabolic Research Group, de Duve Institute, UCLouvain, B-1200, Brussels, Belgium.
  • 11 Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges‑François Leclerc Cancer Center‑UNICANCER, 21079, Dijon, France.
  • 12 ICMUB UMR CNRS 6302, 21079, Dijon, France.
  • 13 Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Croix du Sud 4-5/L7.07.03, B-1348, Louvain-la-Neuve, Belgium.
  • 14 WEL Research Institute, Avenue Pasteur 6, B-1300, Wavre, Belgium.
  • 15 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium. cyril.corbet@uclouvain.be.
  • 16 WEL Research Institute, Avenue Pasteur 6, B-1300, Wavre, Belgium. cyril.corbet@uclouvain.be.
  • # Contributed equally.
PMID: 39890801 DOI: 10.1038/s41467-025-56675-3
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.

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