title: Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 Oxidation.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to additional T790M mutation on EGFR (EGFR(T790M)), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the molecular and biological effects of EGFR(T790M) after redox manipulation.
  
  
  RESULTS
  The basal ROS levels in EGFR(T790M)-containing TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacological agent to elevate ROS, and resulted in EGFR overoxidation, degradation, and apoptosis. By contrast, such responses were lacking in EGFR(WT) cells. Selective EGFR(T790M) degradation was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degradation were confirmed.
  
  
  METHODS
  We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFR(T790M) degradation via specific stimulation of methionine 790 (M790) oxidation. It can be achieved via manipulating redox imbalance between NOX3 and MsrA.
  
  
  CONCLUSIONS
  Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFR(T790M) and EGFR(WT).
authors.affiliation: 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau (SAR), China .
authors.forename: Elaine Lai-Han
authors.initials: EL
authors.lastname: Leung
authors.affiliation: 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau (SAR), China .
authors.forename: Xing-Xing
authors.initials: XX
authors.lastname: Fan
authors.affiliation: 2 Department of Pathology, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong , Hong Kong (SAR), China .
authors.forename: Maria Pik
authors.initials: MP
authors.lastname: Wong
authors.affiliation: 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau (SAR), China .
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Jiang
authors.affiliation: 3 International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou, China .
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau (SAR), China .
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Yao
authors.affiliation: 3 International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou, China .
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Lu
authors.affiliation: 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau (SAR), China .
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhou
authors.affiliation: 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau (SAR), China .
authors.forename: Li-Fong
authors.initials: LF
authors.lastname: Yau
authors.affiliation: 2 Department of Pathology, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong , Hong Kong (SAR), China .
authors.forename: Vicky Pui-Chi
authors.initials: VP
authors.lastname: Tin
authors.affiliation: 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau (SAR), China .
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines / Q000737:chemistry / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077156:Gefitinib; D015870:Gene Expression; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D059748:Proteolysis; D011799:Quinazolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D053119:Benzophenanthridines; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017382:Reactive Oxygen Species; D008715:Methionine; C005705:sanguinarine; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C431570:Nox3 protein, human; D066246:ErbB Receptors; D000077156:Gefitinib