Lipid metabolism drives osimertinib resistance in non-small cell lung cancer

ABSTRACT: Non-small-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 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 multi-omics approach, combining lipidomics with proteomics analyses. We found alterations in processes relating to metabolism, including dysregulated sphingolipid metabolism, lipid peroxidation and ferroptosis. In particular, we identified that OR lines reduce free ceramides in favour 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 sensitivity to osimertinib. Overall, we have identified the glycosphingolipid metabolic pathway as a potential therapeutic target to reinstate sensitivity to osimertinib in NSCLC.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Lung Adenocarcinoma

SUBMITTER: Alex Montoya  

LAB HEAD: Dr Zoe Hall

PROVIDER: PXD071008 | Pride | 2026-03-03

REPOSITORIES: Pride