Disruption of ETV6 leads to TWIST1-dependent progression and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in prostate cancer

Yuan Chin Tsai, Tao Zeng, Wassim Abou-Kheir, Hsiu Lien Yeh, Juan Juan Yin, Yi Chao Lee, Wei Yu Chen, Yen Nien Liu

研究成果: 雜誌貢獻文章

3 引文 斯高帕斯(Scopus)

摘要

Background: ETS variant gene 6 (ETV6) is a putative tumor suppressor and repressed by epidermal growth factor receptor (EGFR) signaling in prostate cancer. Since EGFR antagonists seem ineffective in castration-resistant prostate cancer (CRPC), we aim to study the role of ETV6 in the development of drug resistance. Methods: Etv6 target gene was validated by ChIP and promoter reporter assays. Correlation of ETV6 and TWIST1 was analyzed in human clinical datasets and tissue samples. Migration, invasion, and metastasis assays were used to measure the cellular responses after perturbation of ETV6 -TWIST1 axis. Proliferation and tumor growth in xenograft model were performed to evaluate the drug sensitivities of EGFR-tyrosine kinase inhibitors (TKIs). Results: ETV6 inhibits TWIST1 expression and disruption of ETV6 promotes TWIST1-dependent malignant phenotypes. Importantly, ETV6 is required to the anti-proliferation effects of EGFR-TKIs, partly due to the inhibitory function of ETV6 on TWIST1. We also found that EGFR-RAS signaling is tightly controlled by ETV6, supporting its role in TKI sensitivity. Conclusions: Our study demonstrates that disruption of ETV6 contributes to EGFR-TKI resistance, which is likely due to derepression of TWIST1 and activation of EGFR-RAS signaling. Our results implicate ETV6 as a potential marker for predicting efficacy of an EGFR-targeted anticancer approach. Combination treatment of TWIST1 inhibitors could sensitize the anti-proliferation effects of EGFR-TKIs.
原文英語
文章編號42
期刊Molecular Cancer
17
發行號1
DOIs
出版狀態已發佈 - 二月 19 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

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