Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation
Zehe Ge, Miao Xu, Yuqian Ge, G. Huang, Dongyin Chen, Xiuquan Ye, Yibei Xiao, Hongyu Zhu, Rong Yin, Hua Shen, Gaoxiang Ma, Lian‐Wen Qi, Guining Wei, Dongmei Li, Shaofeng Wei, Meng Zhu, Hongxia Ma, Zhumei Shi, Xiuxing Wang, Xin Ge, Qian Xu
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 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.