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

• DOI: 10.1038/s41467-025-56675-3
• Publication Date: 2025-02-01T01:21:56Z
• Authors: Valentin Van den ...; 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
• Keywords: Science; Q; Human medicine; Article

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.