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

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...

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Main Authors: 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, Cyril Corbet
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56675-3
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Summary: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.
ISSN:2041-1723

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