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

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.