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.