Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation.

EGFR 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 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 and inducing the degradation of EGFR. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFR-harboring NSCLCs and delays the acquisition of the EGFR mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFR mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFR-driven TKI resistance by directly targeting G6PD.