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EGFRT790M 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 EGFRT790M 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 EGFRT790M and inducing the degradation of EGFRT790M. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFRT790M-harboring NSCLCs and delays the acquisition of the EGFRT790M mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFRT790M mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFRT790M-driven TKI resistance by directly targeting G6PD. [Display omitted] • Quercetin promotes EGFRT790M degradation through enhancing M790 oxidation • Quercetin inhibits G6PD to reduce NADPH production and to increase EGFR M790 oxidation • Targeting G6PD by quercetin sensitizes EGFRT790M-harboring NSCLC to gefitinib • Quercetin delays the EGFRT790M mutation acquisition during gefitinib treatment Ge et al. report that quercetin is a natural inhibitor of G6PD, which selectively promotes degradation of EGFRT790M through reducing intracellular NADPH levels. Inhibition of G6PD by quercetin delays acquisition of EGFRT790M mutation and synergistically sensitizes therapeutic effects of gefitinib on NSCLCs. [ABSTRACT FROM AUTHOR]

Radiotherapy is a standard-of-care treatment approach for glioblastoma (GBM) patients, but therapeutic resistance to radiotherapy remains a major challenge. Here we demonstrate that diallyl trisulfide (DATS) directly conjugates with cysteine (C) 32 and C35 (C32/35) residues of thioredoxin 1 (Trx1) through Michael addition reactions. Due to localizing in activity center of Trx1, the conjugation between DATS and C32/35 results in inhibition of Trx1 activity, therefore disturbing thioredoxin system and leading to accumulated levels of reactive oxygen species (ROS). High levels of Trx1 expression are correlated with poor prognosis of glioma patients. Notably, we reveal that DATS synergistically enhances irradiation (IR)-induced ROS accumulation, apoptosis, DNA damage, as well as inhibition of tumor growth of GBM cells. These findings highlight the potential benefits of DATS in sensitizing radiotherapy of GBM patients. [Display omitted] • Thioredoxin 1 (Trx1) was identified as the direct target of Diallyl trisulfide (DATS). • DATS conjugates with C32/35 residues of Trx1 through Michael addition reactions. • The conjugation of DATS with Trx1 inhibited Trx1 activity and disturbed redox balance. • DATS synergistically enhanced the radiotherapy effects of GBM cells. [ABSTRACT FROM AUTHOR]