Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• EGFR T790M mutations confer resistance to first-generation tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC).
• Limited therapeutic strategies exist to overcome TKI resistance or delay the emergence of EGFR T790M mutations.

Purpose of the Study:

• To investigate the mechanism by which quercetin overcomes EGFR T790M-driven TKI resistance.
• To explore quercetin's potential as a therapeutic agent in combination with TKIs for NSCLC.

Main Methods:

• Biochemical assays to determine quercetin's interaction with glucose-6-phosphate dehydrogenase (G6PD).
• Measurement of intracellular NADPH levels and assessment of EGFR T790M oxidation.
• Evaluation of quercetin's synergistic effect with gefitinib in EGFR T790M-harboring NSCLC models.
• Correlation analysis of G6PD expression with patient prognosis and mutation timing.

Main Results:

• Quercetin directly binds to G6PD, inhibiting its enzymatic activity by blocking NADP+ binding.
• Quercetin reduces intracellular NADPH levels, impairing the reduction of EGFR T790M oxidation.
• Quercetin induces degradation of EGFR T790M and synergistically enhances gefitinib's therapeutic effect.
• High G6PD expression correlates with poor prognosis and earlier emergence of EGFR T790M mutations in NSCLC patients.

Conclusions:

• Quercetin targets G6PD to overcome EGFR T790M-mediated TKI resistance in NSCLC.
• Quercetin enhances the efficacy of gefitinib and delays the acquisition of TKI resistance.
• G6PD is a potential therapeutic target for managing TKI-resistant NSCLC.