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

Valentin Van den Bossche1,2, Julie Vignau1, Engy Vigneron1

  • 1Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium.

Nature Communications
|January 31, 2025
PubMed

Insights

Acquired resistance to anti-epidermal growth factor receptor (EGFR) therapy in head and neck squamous cell carcinoma (HNSCC) involves lipid metabolism reprogramming. Targeting fatty acid oxidation via carnitine palmitoyltransferase 1A (CPT1A) or peroxisome proliferator-activated receptor alpha (PPARα) can overcome this resistance.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer resistance mechanisms

Background:

  • Anti-epidermal growth factor receptor (EGFR) therapy, such as cetuximab, offers limited clinical benefit for head and neck squamous cell carcinoma (HNSCC) due to acquired resistance.
  • Secondary resistance mechanisms frequently emerge, hindering treatment efficacy in locally advanced or recurrent/metastatic HNSCC.

Purpose of the Study:

  • To investigate the metabolic alterations driving secondary resistance to anti-EGFR therapy in HNSCC.
  • To identify potential therapeutic targets to overcome acquired resistance to cetuximab in HNSCC.

Main Methods:

  • Analysis of cetuximab-resistant HNSCC cell lines.
  • Assessment of metabolic pathways, including lipid metabolism and glycolysis.
  • Pharmacological inhibition of key metabolic enzymes (CPT1A, PPARα) in vitro and in vivo (tumor xenografts).
  • Correlation of PPARα-related gene signatures with clinical data from HNSCC patients.

Main Results:

  • Cetuximab-resistant HNSCC cells exhibit peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming.
  • Increased fatty acid uptake and oxidation capacities were observed, while glycolysis remained unchanged.
  • Pharmacological inhibition of carnitine palmitoyltransferase 1A (CPT1A) or PPARα sensitized resistant cells in 3D spheroids and mouse xenografts.
  • A PPARα-related gene signature in human clinical datasets correlated with reduced response to anti-EGFR therapy and poorer survival in HNSCC patients.

Conclusions:

  • Lipid metabolism rewiring, mediated by PPARα, is a significant non-genetic resistance mechanism in HNSCC.
  • Targeting fatty acid oxidation pathways (CPT1A, PPARα) represents a promising strategy to overcome acquired resistance to anti-EGFR therapy.
  • The PPARα pathway serves as a clinically relevant biomarker for predicting response to anti-EGFR therapy and patient survival in HNSCC.

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