1. Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation.
- Author
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Ge, Zehe, Xu, Miao, Ge, Yuqian, Huang, Guang, Chen, Dongyin, Ye, Xiuquan, Xiao, Yibei, Zhu, Hongyu, Yin, Rong, Shen, Hua, Ma, Gaoxiang, Qi, Lianwen, Wei, Guining, Li, Dongmei, Wei, Shaofeng, Zhu, Meng, Ma, Hongxia, Shi, Zhumei, Wang, Xiuxing, and Ge, Xin
- Abstract
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 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]- Published
- 2023
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