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Addressing Clinical Limitations of Glutaminase Inhibitors: Novel Strategies for Osimertinib-Resistant Lung Cancer by
Jiali Huang1,2, Xiankang Zhang1, Hui Zhang1
1Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
Abstract:
Overcoming acquired resistance to Osimertinib remains a critical challenge in treating NSCLC. This research indicates that Osimertinib-resistant cells exhibit a strong dependence on glutamine metabolism. However, targeting GLS1 shows limited anticancer effects, probably because it cannot fully block the glutamine metabolic pathway. The investigation reveals that a more effective strategy involves simultaneously inhibiting both ASCT2 and GLS1. After confirming the efficacy of this dual-targeting approach against Osimertinib-resistant cells in preclinical models, the potential of utilizing a broad-spectrum glutamine metabolism antagonist is further explored to achieve superior antitumor efficacy. DON, broad-spectrum glutamine antagonist, presents toxicity issues. Herein, the high NQO1 expression in Osimertinib-resistant NSCLC cells is leveraged to design an NQO1-responsive DON prodrug, 10e (LBJ-10e). This prodrug demonstrates superior safety compared to natural DON and greater antitumor activity against resistant tumors compared to the clinical phase II drug DRP104. These findings may address the clinical limitations of GLS1 allosteric inhibitors and underscore prodrug strategies in effectively treating Osimertinib-resistant lung cancer, providing a foundation for future clinical trials.
Insights
Targeting glutamine metabolism by inhibiting ASCT2 and GLS1 offers a new strategy against Osimertinib-resistant lung cancer. An NQO1-responsive prodrug, 10e, shows improved safety and efficacy in preclinical models.
Area of Science:
- Oncology
- Metabolic pathways
- Drug development
Background:
- Acquired resistance to Osimertinib is a major challenge in non-small cell lung cancer (NSCLC) treatment.
- Osimertinib-resistant NSCLC cells display heightened dependence on glutamine metabolism.
- Targeting glutaminase 1 (GLS1) alone has limited efficacy due to incomplete pathway blockade.
Purpose of the Study:
- To investigate dual inhibition of ASCT2 and GLS1 for overcoming Osimertinib resistance.
- To explore the potential of a broad-spectrum glutamine antagonist.
- To develop a targeted prodrug strategy for improved safety and efficacy.
Main Methods:
- Preclinical models of Osimertinib-resistant NSCLC were used.
- Dual targeting of ASCT2 and GLS1 was assessed.
- An NQO1-responsive DON prodrug (10e) was designed and evaluated.
- Safety and antitumor activity of 10e were compared to DON and DRP104.
Main Results:
- Simultaneous inhibition of ASCT2 and GLS1 showed efficacy against resistant cells.
- The NQO1-responsive prodrug 10e demonstrated enhanced safety over natural DON.
- 10e exhibited superior antitumor activity compared to DRP104 in resistant tumors.
Conclusions:
- Dual targeting of glutamine metabolism is a promising strategy for Osimertinib-resistant NSCLC.
- An NQO1-responsive DON prodrug (10e) offers a potentially safer and more effective therapeutic option.
- Prodrug strategies leveraging specific tumor markers may overcome limitations of existing treatments for resistant lung cancer.
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