Fiche publication
Date publication
février 2025
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BOIDOT Romain
Tous les auteurs :
Van den Bossche V, Vignau J, Vigneron E, Rizzi I, Zaryouh H, Wouters A, Ambroise J, Van Laere S, Beyaert S, Helaers R, van Marcke C, Mignion L, Lepicard EY, Jordan BF, Guilbaud C, Lowyck O, Dahou H, Mendola A, Desgres M, Aubert L, Gerin I, Bommer GT, Boidot R, Vermonden P, Warnant A, Larondelle Y, Machiels JP, Feron O, Schmitz S, Corbet C
Lien Pubmed
Résumé
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.
Mots clés
Humans, Animals, Cetuximab, pharmacology, ErbB Receptors, metabolism, Drug Resistance, Neoplasm, genetics, Lipid Metabolism, drug effects, Squamous Cell Carcinoma of Head and Neck, drug therapy, PPAR alpha, metabolism, Cell Line, Tumor, Mice, Head and Neck Neoplasms, drug therapy, Xenograft Model Antitumor Assays, Carnitine O-Palmitoyltransferase, metabolism, Fatty Acids, metabolism, Gene Expression Regulation, Neoplastic, drug effects, Female, Metabolic Reprogramming
Référence
Nat Commun. 2025 02 1;16(1):1237
