Abstract
Several different mechanisms are implicated in the resistance of lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and only few have been functionally investigated. Here, using genetically knocked out EGFR and TKI-resistant lung cancer cells, we show that loss of wild-type EGFR attenuates cell proliferation, migration and 3D-spheroid formation, whereas loss of mutant EGFR or resistance to TKIs reinforces those processes. Consistently, disruption of wild-type EGFR leads to suppression of HER2/HER3, while mutant EGFR ablation or resistance to TKIs increases HER2/HER3 expression, compensating for EGFR loss. Furthermore, HER2/HER3 nuclear translocation mediates overexpression of cyclin D1, leading to tumor cell survival and drug resistance. Cyclin D1/CDK4/6 inhibition resensitizes erlotinib-resistant (ER) cells to erlotinib. Analysis of cyclin D1 expression in patients with non-small cell lung carcinoma (NSCLC) showed that its expression is negatively associated with overall survival and disease-free survival. Our results provide biological and mechanistic insights into targeting EGFR and TKI resistance.
Keywords:
Cyclin D1; Drug resistant; EGFR, Tyrosine kinase inhibitors; HER2; Lung cancer.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / therapeutic use
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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 / mortality
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cyclin D1 / genetics*
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase 4 / genetics
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / genetics
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Cyclin-Dependent Kinase 6 / metabolism
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Drug Resistance, Neoplasm / genetics
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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ErbB Receptors / deficiency
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ErbB Receptors / genetics
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Erlotinib Hydrochloride / therapeutic use
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Gene Expression Regulation, Neoplastic*
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics*
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Protein Kinase Inhibitors / therapeutic use
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Receptor, ErbB-2 / genetics*
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-3 / genetics*
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Receptor, ErbB-3 / metabolism
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Signal Transduction
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Spheroids, Cellular / drug effects
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Spheroids, Cellular / metabolism
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Spheroids, Cellular / pathology
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Survival Analysis
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Transcriptional Activation
Substances
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Antineoplastic Agents
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CCND1 protein, human
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Protein Kinase Inhibitors
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Cyclin D1
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Erlotinib Hydrochloride
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EGFR protein, human
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ERBB2 protein, human
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ERBB3 protein, human
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ErbB Receptors
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Receptor, ErbB-2
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Receptor, ErbB-3
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CDK4 protein, human
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CDK6 protein, human
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6