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

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  • Valentin Van den bossche

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
    King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc)

  • Julie Vignau

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Engy Vigneron

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Isabella Rizzi

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Hannah Zaryouh

    (Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp)

  • An Wouters

    (Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp)

  • Jérôme Ambroise

    (Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Steven Van Laere

    (GZA Ziekenhuizen)

  • Simon Beyaert

    (King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
    Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
    Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc)

  • Raphaël Helaers

    (UCLouvain)

  • Cédric van Marcke

    (King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
    Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Lionel Mignion

    (UCLouvain)

  • Elise Y. Lepicard

    (UCLouvain)

  • Bénédicte F. Jordan

    (UCLouvain)

  • Céline Guilbaud

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Olivier Lowyck

    (King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
    Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Hajar Dahou

    (Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Antonella Mendola

    (Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Manon Desgres

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Léo Aubert

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain)

  • Isabelle Gerin

    (UCLouvain)

  • Guido T. Bommer

    (UCLouvain)

  • Romain Boidot

    (Georges‑François Leclerc Cancer Center‑UNICANCER
    ICMUB UMR CNRS 6302)

  • Perrine Vermonden

    (Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain)

  • Aurélien Warnant

    (Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain)

  • Yvan Larondelle

    (Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain)

  • Jean-Pascal Machiels

    (King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
    Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
    Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc)

  • Olivier Feron

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
    WEL Research Institute)

  • Sandra Schmitz

    (King Albert II Cancer Institute, Department of Medical Oncology, Cliniques Universitaires Saint-Luc
    Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
    Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc)

  • Cyril Corbet

    (Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain
    WEL Research Institute)

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.

Suggested Citation

  • 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 & Lion, 2025. "PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56675-3
    DOI: 10.1038/s41467-025-56675-3
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    2. Gloria Pascual & Alexandra Avgustinova & Stefania Mejetta & Mercè Martín & Andrés Castellanos & Camille Stephan-Otto Attolini & Antoni Berenguer & Neus Prats & Agustí Toll & Juan Antonio Hueto & Coro , 2017. "Targeting metastasis-initiating cells through the fatty acid receptor CD36," Nature, Nature, vol. 541(7635), pages 41-45, January.
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