Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition

Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resi...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-06, Vol.77 (11), p.3013-3026
Main Authors: Hwang, Wen, Chiu, Yu-Fan, Kuo, Ming-Han, Lee, Kuan-Lin, Lee, An-Chun, Yu, Chia-Cherng, Chang, Junn-Liang, Huang, Wen-Chien, Hsiao, Shih-Hsin, Lin, Sey-En, Chou, Yu-Ting
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - genetics
Adenocarcinoma of Lung
Animals
Antineoplastic Agents - metabolism
Carcinoma, Non-Small-Cell Lung - genetics
Cell Line, Tumor
Correlation analysis
Epidermal growth factor receptors
Epithelial-Mesenchymal Transition
ErbB Receptors
Female
Humans
Inhibitors
Invasiveness
Kinases
Lung cancer
Lung Neoplasms - genetics
Medical prognosis
Mesenchyme
Mice
Mice, Nude
Mutation
Protein-tyrosine kinase
Signal Transduction
Tumor cells
Xenografts
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Summary:Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-16-3168