Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides
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Aniline Compounds
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Animals
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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Antineoplastic Agents / pharmacology*
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Cadherins / antagonists & inhibitors
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Cadherins / biosynthesis
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Cadherins / genetics
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Drug Resistance, Neoplasm / genetics*
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Drug Resistance, Neoplasm / physiology
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Drug Screening Assays, Antitumor
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / genetics
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Epithelial-Mesenchymal Transition / physiology*
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ErbB Receptors / genetics
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Gefitinib / pharmacology*
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Gene Expression Regulation, Neoplastic / drug effects
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / pathology
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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RNA Interference
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RNA, Small Interfering / pharmacology
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Specific Pathogen-Free Organisms
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Ubiquitin-Protein Ligases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / biosynthesis
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Ubiquitin-Protein Ligases / genetics
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Vimentin / antagonists & inhibitors
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Vimentin / biosynthesis
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Vimentin / genetics
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Zinc Finger E-box-Binding Homeobox 1 / biosynthesis
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Zinc Finger E-box-Binding Homeobox 1 / genetics
Substances
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Acrylamides
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Aniline Compounds
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Antigens, CD
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Antineoplastic Agents
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CDH1 protein, human
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Cadherins
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Histone Deacetylase Inhibitors
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Neoplasm Proteins
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Piperazines
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Protein Kinase Inhibitors
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RNA, Small Interfering
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VIM protein, human
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Vimentin
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1
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osimertinib
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CBLL1 protein, human
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Ubiquitin-Protein Ligases
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EGFR protein, human
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ErbB Receptors
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Gefitinib