PPARα-mediated Lipid Metabolism Reprogramming Supports Anti-EGFR Therapy Resistance in Head and Neck Squamous Cell Carcinoma

Overview

Journal Nat Commun

Date 2025 Jan 31

PMID 39890801

Authors

Valentin Van den Bossche

Julie Vignau

Engy Vigneron

Isabella Rizzi

Hannah Zaryouh

An Wouters

Jerome Ambroise

Steven Van Laere

Simon Beyaert

Raphael Helaers

Cedric van Marcke

Lionel Mignion

Elise Y Lepicard

Benedicte F Jordan

Celine Guilbaud

Olivier Lowyck

Hajar Dahou

Antonella Mendola

Manon Desgres

Leo Aubert

Isabelle Gerin

Guido T Bommer

Romain Boidot

Perrine Vermonden

Aurelien Warnant

Yvan Larondelle

Jean-Pascal Machiels

Olivier Feron

Sandra Schmitz

Cyril Corbet

Affiliations

Soon will be listed here.

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.

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