PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma PMID: 39890801

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
16. WEL Research Institute, Avenue Pasteur 6, B-1300, Wavre, Belgium. [email protected].
# Contributed equally.

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.