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Updated: Jun 30, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC
Silvia La Monica1, Federica Vacondio2, Kamal Eltayeb1
1Department of Medicine and Surgery, University of Parma, 43126, Parma, Italy.
Abstract:
The EGFR tyrosine kinase inhibitor osimertinib has been approved for the first-line treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patients. Despite its efficacy, patients develop resistance. Mechanisms of resistance are heterogeneous and not fully understood, and their characterization is essential to find new strategies to overcome resistance. Ceramides are well-known regulators of apoptosis and are converted into glucosylceramides (GlcCer) by glucosylceramide synthase (GCS). A higher content of GlcCers was observed in lung pleural effusions from NSCLC patients and their role in osimertinib-resistance has not been documented. The aim of this study was to determine the therapeutic potential of inhibiting GCS in NSCLC EGFR-mutant models resistant to osimertinib in vitro and in vivo. Lipidomic analysis showed a significant increase in the intracellular levels of glycosylceramides, including GlcCers in osimertinib resistant clones compared to sensitive cells. In resistant cells, the GCS inhibitor PDMP caused cell cycle arrest, inhibition of 2D and 3D cell proliferation, colony formation and migration capability, and apoptosis induction. The intratumoral injection of PDMP completely suppressed the growth of OR xenograft models. This study demonstrated that dysregulation of ceramide metabolism is involved in osimertinib-resistance and targeting GCS may be a promising therapeutic strategy for patients progressed to osimertinib.
Insights
Targeting glucosylceramide synthase (GCS) shows promise for overcoming osimertinib resistance in EGFR-mutated Non-Small Cell Lung Cancer (NSCLC). Inhibiting GCS disrupts cancer cell growth and induces apoptosis, offering a new therapeutic avenue for resistant NSCLC tumors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osimertinib is a first-line treatment for EGFR-mutated Non-Small Cell Lung Cancer (NSCLC), but resistance develops.
- Mechanisms of osimertinib resistance in NSCLC are not fully understood.
- Ceramides regulate apoptosis; glucosylceramides (GlcCer) are derived from ceramides via glucosylceramide synthase (GCS).
Purpose of the Study:
- To investigate the role of ceramide metabolism in osimertinib resistance in NSCLC.
- To evaluate the therapeutic potential of inhibiting GCS in osimertinib-resistant NSCLC models.
Main Methods:
- Lipidomic analysis of osimertinib-sensitive and resistant NSCLC cells.
- In vitro studies using the GCS inhibitor PDMP on resistant cells (cell cycle, proliferation, migration, apoptosis).
- In vivo studies involving intratumoral injection of PDMP in xenograft models of osimertinib-resistant NSCLC.
Main Results:
- Osimertinib-resistant NSCLC cells exhibited increased intracellular glycosylceramides, including GlcCers.
- PDMP treatment induced cell cycle arrest, inhibited proliferation, colony formation, and migration, and triggered apoptosis in resistant cells.
- Intratumoral PDMP administration completely suppressed tumor growth in vivo.
Conclusions:
- Dysregulation of ceramide metabolism, specifically increased GlcCers, is implicated in osimertinib resistance in NSCLC.
- Inhibiting GCS is a potential therapeutic strategy to overcome osimertinib resistance in NSCLC patients.
- Targeting GCS offers a promising approach for NSCLC patients who have progressed on osimertinib therapy.
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