2. Academic Validation
  3. Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation

Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation

  • Cell Rep. 2023 Nov 10;42(11):113417. doi: 10.1016/j.celrep.2023.113417.
Zehe Ge 1,  Miao Xu 1,  Yuqian Ge 1,  Guang Huang 2,  Dongyin Chen 3,  Xiuquan Ye 4,  Yibei Xiao 4,  Hongyu Zhu 5,  Rong Yin 5,  Hua Shen 6,  Gaoxiang Ma 7,  Lianwen Qi 8,  Guining Wei 9,  Dongmei Li 9,  Shaofeng Wei 10,  Meng Zhu 11,  Hongxia Ma 11,  Zhumei Shi 12,  Xiuxing Wang 13,  Xin Ge 1,  Xu Qian 14
Affiliations

Affiliations

  • 1 Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
  • 2 Department of Health Inspection and Quarantine, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 5 Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing 21009, China.
  • 6 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Oncology, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
  • 7 Clinical Metabolomics Center, China Pharmaceutical University, Nanjing 211198, China.
  • 8 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Clinical Metabolomics Center, China Pharmaceutical University, Nanjing 211198, China.
  • 9 Department of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning 530022, China.
  • 10 The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Provincial Engineering Research Center of Ecological Food Innovation, School of Public Health, Guizhou Medical University, Guiyang 550025, China.
  • 11 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 12 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
  • 13 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 14 Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing 21009, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address: [email protected].
PMID: 37950872 DOI: 10.1016/j.celrep.2023.113417
Abstract

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.

Keywords

CP: Cancer; EGFR(T790M); G6PD; MsrA; gefitinib; glucose-6-phosphate dehydrogenase; methionine oxidization; methionine reductase A; quercetin.

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