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Altered Sphingolipid Metabolism is Associated with Osimertinib Resistance in Nonsmall-Cell Lung Cancer

Julia Babuta1, Aleksandra Gruevska1, Chiharu Wickremesinghe2

  • 1Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, United Kingdom.

Journal of Proteome Research
|April 16, 2026
PubMed

Insights

Drug resistance to osimertinib in lung cancer is linked to altered lipid metabolism. Targeting glycosphingolipid pathways may restore sensitivity to this important cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Nonsmall-cell lung cancer (NSCLC) is the most common type of lung cancer.
  • Epidermal growth factor receptor mutations (EGFRm) are key targets for NSCLC treatment with tyrosine kinase inhibitors (TKIs).
  • Osimertinib resistance is a significant clinical challenge in advanced NSCLC, with metabolic dysregulation implicated.

Purpose of the Study:

  • To investigate the role of lipid metabolism in the development of osimertinib resistance (OR) in NSCLC.
  • To identify specific metabolic pathways contributing to OR.
  • To explore potential therapeutic strategies to overcome osimertinib resistance.

Main Methods:

  • Utilized pharmacologically-induced resistant NSCLC cellular models.
  • Employed a multiomics approach combining lipidomics and proteomics analyses.
  • Investigated the impact of inhibiting ceramide-to-glucosylceramide conversion on osimertinib sensitivity.

Main Results:

  • Identified dysregulated sphingolipid metabolism in osimertinib-resistant NSCLC cells.
  • Observed a metabolic shift from free ceramides to complex glycosphingolipids in resistant cells.
  • Demonstrated that combining osimertinib with a glucosylceramide synthase inhibitor (D-PDMP) re-sensitized resistant cells to osimertinib, by preventing ceramide-mediated apoptosis.

Conclusions:

  • Glycosphingolipid metabolism plays a critical role in osimertinib resistance in NSCLC.
  • The metabolic shift to glycosphingolipids promotes survival by inhibiting ceramide-induced apoptosis.
  • Targeting the glycosphingolipid pathway represents a promising strategy to overcome osimertinib resistance and improve treatment outcomes in NSCLC.
Keywords:
ceramideglucosylceramidaseglycosphingolipidlipidomicsmultiomicsnonsmall-cell lung cancersphingolipid, drug resistance

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