EGFRT790M 突变导致非小细胞肺癌 (NSCLC) 患者对第一代酪氨酸激酶抑制剂 (TKI) 产生耐药性。然而，使第一个 TKI 敏感和延迟 EGFRT790M 突变体出现的治疗选择是有限的。在这项研究中，我们发现槲皮素直接与葡萄糖-6-磷酸脱氢酶（G6PD）结合，并通过竞争性地消除催化域中的 NADP 结合来抑制其酶活性。这种抑制随后降低细胞内 NADPH 水平，导致甲硫氨酸还原酶 A (MsrA) 的底物不足，无法减少 EGFRT790M 的 M790 氧化并诱导 EGFRT790M 降解。槲皮素可协同增强吉非替尼对携带 EGFRT790M 的 NSCLC 的治疗效果，并延迟 EGFRT790M 突变的获得。值得注意的是，高水平的 G6PD 表达与 NSCLC 患者的不良预后和 EGFRT790M 突变的出现时间相关。这些发现强调了槲皮素通过直接靶向 G6PD 来克服 EGFRT790M 驱动的 TKI 耐药性的潜在影响。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.