Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation

EGFR^T790M mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the therapeutic options for sensitizing first TKIs and delaying the emergence of EGFR^T790M mutant are limited. In this study, we show that quercetin directly binds with glucose-6-phosphate dehydrogenase (G6PD) and inhibits its enzymatic activity through competitively abrogating NADP⁺ binding in the catalytic domain. This inhibition subsequently reduces intracellular NADPH levels, resulting in insufficient substrate for methionine reductase A (MsrA) to reduce M790 oxidization of EGFR^T790M and inducing the degradation of EGFR^T790M. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFR^T790M-harboring NSCLCs and delays the acquisition of the EGFR^T790M mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFR^T790M mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFR^T790M-driven TKI resistance by directly targeting G6PD.