Expression of neuroendocrine factor VGF in lung cancer cells confers resistance to EGFR kinase inhibitors and triggers epithelial-to-mesenchymal transition

Wen Hwang, Yu Fan Chiu, Ming Han Kuo, Kuan Lin Lee, An Chun Lee, Chia Cherng Yu, Junn Liang Chang, Wen Chien Huang, Shih Hsin Hsiao, Sey En Lin, Yu Ting Chou

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3013-3026
Number of pages14
JournalCancer Research
Volume77
Issue number11
DOIs
Publication statusPublished - Jun 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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