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Updated: Nov 9, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
VPS34 suppression reverses osimertinib resistance via simultaneously inhibiting glycolysis and autophagy
Hengyi Chen1, Conghua Lu1, Caiyu Lin1
1Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China.
Abstract:
Autophagy and glycolysis are associated with osimertinib resistance. The energy complement and dynamic balance between these two processes make it difficult to block the process of drug resistance; breaking the complementary relationship between them may effectively overcome drug resistance. However, the exact mechanisms and the key players for regulating autophagy and glycolysis remain unclear. In this study, we demonstrate that autophagy and glycolysis levels in osimertinib-resistant cells were markedly higher than parental cells, and a dynamic balance existed between them. Inhibition of the class III phosphoinositide 3-kinase vacuolar protein sorting 34 (VPS34) with 3-methyladenine or small interfering RNA can not only inhibit abnormally enhanced autophagy but also inhibit glycolysis by inhibiting the location of epidermal growth factor receptor (EGFR) and the expression of hexokinase II. By demonstrating that VPS34 is the key player controlling autophagy and glycolysis simultaneously, our study may provide a new strategy for overcoming osimertinib resistance for treatment of EGFR-mutant non-small cell lung cancer patients.
Insights
Targeting vacuolar protein sorting 34 (VPS34) can overcome osimertinib resistance in non-small cell lung cancer by inhibiting both autophagy and glycolysis. This dual inhibition offers a new therapeutic strategy for EGFR-mutant patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osimertinib resistance is a significant challenge in treating EGFR-mutant non-small cell lung cancer (NSCLC).
- Autophagy and glycolysis are implicated in osimertinib resistance, but their interplay and regulatory mechanisms remain poorly understood.
- A dynamic balance between autophagy and glycolysis contributes to drug resistance, necessitating strategies to disrupt this relationship.
Purpose of the Study:
- To investigate the roles of autophagy and glycolysis in osimertinib resistance in EGFR-mutant NSCLC.
- To identify key regulators controlling both autophagy and glycolysis pathways.
- To explore VPS34 as a potential therapeutic target for overcoming osimertinib resistance.
Main Methods:
- Comparative analysis of autophagy and glycolysis levels in osimertinib-resistant versus parental NSCLC cells.
- Pharmacological inhibition of vacuolar protein sorting 34 (VPS34) using 3-methyladenine.
- Genetic inhibition of VPS34 using small interfering RNA (siRNA).
- Assessment of epidermal growth factor receptor (EGFR) localization and hexokinase II expression.
Main Results:
- Osimertinib-resistant cells exhibited significantly elevated autophagy and glycolysis levels compared to parental cells.
- A dynamic balance between autophagy and glycolysis was observed in resistant cells.
- VPS34 inhibition by 3-methyladenine or siRNA effectively suppressed both enhanced autophagy and glycolysis.
- VPS34 inhibition reduced EGFR localization and hexokinase II expression, key factors in glycolysis.
Conclusions:
- VPS34 is a critical regulator controlling both autophagy and glycolysis simultaneously in osimertinib-resistant NSCLC.
- Targeting VPS34 presents a promising new strategy to overcome osimertinib resistance.
- This approach could benefit patients with EGFR-mutant non-small cell lung cancer.
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