PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma
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.
Authors
- Cyril Corbet (ORCID: https://orcid.org/0000-0001-8795-9131)
- Guido T. Bommer (ORCID: https://orcid.org/0000-0001-6898-4884)
- Bénédicte F. Jordan (ORCID: https://orcid.org/0000-0002-7126-2206)
- Antonella Mendola (ORCID: https://orcid.org/0009-0006-2462-1110)
- Elise Y. Lepicard (ORCID: https://orcid.org/0000-0002-9021-2060)
- Yvan Larondelle (ORCID: https://orcid.org/0000-0001-7770-6747)
- I Rizzi
- Sandra Schmitz (ORCID: https://orcid.org/0000-0002-9943-2078)
- An Wouters (ORCID: https://orcid.org/0000-0001-7771-1239)
- Valentin Van den Bossche (ORCID: https://orcid.org/0000-0001-5443-6641)
- Isabelle Gerin (ORCID: https://orcid.org/0009-0000-0331-8207)
- Hannah Zaryouh (ORCID: https://orcid.org/0000-0002-4567-1399)
- Raphaël Helaers (ORCID: https://orcid.org/0000-0002-7046-7867)
- Céline Guilbaud
- Hajar Dahou (ORCID: https://orcid.org/0009-0001-4479-5760)
- Manon Desgres (ORCID: https://orcid.org/0000-0003-2777-9010)
- Olivier Féron (ORCID: https://orcid.org/0000-0001-5360-0286)
- Simon P. Beyaert (ORCID: https://orcid.org/0000-0002-7241-526X)
- Lionel Mignion
- Perrine Vermonden
- Jean‐Pascal Machiels (ORCID: https://orcid.org/0000-0001-6369-9742)
- Romain Boidot (ORCID: https://orcid.org/0000-0001-9956-1737)
- Steven Van Laere (ORCID: https://orcid.org/0000-0002-2640-0040)
- Cédric van Marcke (ORCID: https://orcid.org/0000-0003-3454-0630)
- Julie Vignau (ORCID: https://orcid.org/0000-0002-0117-1958)
- Jérôme Ambroise (ORCID: https://orcid.org/0000-0002-1218-6143)
- Léo Aubert (ORCID: https://orcid.org/0000-0003-1499-0853)
- Achille Warnant
- Olivier Lowyck (ORCID: https://orcid.org/0009-0007-7320-1005)
- Engy Vigneron
Institutions
- Centre National de la Recherche Scientifique (FR)
- Cliniques Universitaires Saint-Luc (BE)
- University of Antwerp (BE)
- GZA Ziekenhuizen Campus Sint-Augustinus (BE)
- Centre Georges François Leclerc (FR)
- de Duve Institute (BE)
- Laboratoire Interdisciplinaire Carnot de Bourgogne (FR)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Directorate-General Joint Research Centre (BE)
- UCLouvain (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1038/s41467-025-56675-3
- Citations
- 15
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 14.04
Funders
- Université Catholique de Louvain
- Fonds De La Recherche Scientifique - FNRS
- Fonds Joseph Maisin
- Fondation contre le Cancer
- Walloon excellence in life sciences and biotechnology