Altered sphingolipid metabolism is associated with osimertinib resistance in non-small cell lung cancer
Author(s)
Type
Journal Article
Abstract
Nonsmall-cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases. Epidermal growth factor receptor mutations (EGFRm) occur in 15 and 40% of NSCLC in Western and Asian populations, respectively. Current treatment for advanced NSCLC targets EGFRm with tyrosine kinase inhibitors (TKIs). Osimertinib is a third-generation EGFR-TKI now used as a first-line treatment in advanced/metastatic NSCLC; however, drug resistance frequently develops. Dysregulation of metabolism has been suggested to play a role in the development of drug resistance. Here, we investigated the role of lipid metabolism in the development of osimertinib resistance (OR) using pharmacologically-induced resistant cellular models. We used a multiomics approach, combining lipidomics with proteomics analyses. We found alterations in processes relating to metabolism, such as dysregulated sphingolipid metabolism. In particular, we identified that OR lines reduce free ceramides in favor of complex glycosphingolipids. Mechanistically, this metabolic shift avoids ceramide-mediated apoptosis via caspase-3 activation. Importantly, when we combined osimertinib with D-PDMP, an inhibitor of the key enzyme responsible for the conversion of ceramide to glucosylceramide, we increased the sensitivity to osimertinib. Overall, we have identified the glycosphingolipid metabolic pathway as a potential therapeutic target to reinstate sensitivity to osimertinib in NSCLC.
Date Issued
2026-05-01
Date Acceptance
2026-04-08
Citation
Journal of Proteome Research, 2026, 25 (5), pp.2569-2580
ISSN
1535-3893
Publisher
American Chemical Society
Start Page
2569
End Page
2580
Journal / Book Title
Journal of Proteome Research
Volume
25
Issue
5
Copyright Statement
Copyright © 2026 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 .
License URL
Identifier
10.1021/acs.jproteome.6c00216
Subjects
nonsmall-cell lung cancer
lipidomics
glycosphingolipid
ceramide
sphingolipid
drug resistance
multiomics
glucosylceramidase
Publication Status
Published
Date Publish Online
2026-04-16