Cancer Medicine (Sep 2018)

The regulatory role of APE1 in epithelial‐to‐mesenchymal transition and in determining EGFR‐TKI responsiveness in non‐small‐cell lung cancer

  • Xiao Yang,
  • Yu Peng,
  • Xuan Jiang,
  • Xianfeng Lu,
  • Wei Duan,
  • Shiheng Zhang,
  • Nan Dai,
  • Jinlu Shan,
  • Yan Feng,
  • Xuemei Li,
  • Yi Cheng,
  • Yuxin Yang,
  • Laura Baugh,
  • Gianluca Tell,
  • Dong Wang,
  • Mengxia Li

DOI
https://doi.org/10.1002/cam4.1717
Journal volume & issue
Vol. 7, no. 9
pp. 4406 – 4419

Abstract

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Abstract Background Epithelial‐to‐mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor‐β (TGF‐β), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR‐TKI responsiveness in NSCLC. Methods The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR‐TKI treatment. The correlation between APE1 expression and progression‐free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR‐TKIs was measured by exogenous manipulation of APE1 in EGFR‐TKI‐sensitive and EGFR‐TKI‐resistant cells. Results We indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), with no difference in initial response rate to EGFR‐TKIs. We observed that APE1 protein level was significantly increased in EGFR‐TKI‐resistant cells and was associated with downregulated E‐cadherin and upregulated vimentin. The EMT phenotype, as well as the levels of TGF‐β, was suppressed in APE1 knockdown HCC827/IR and PC‐9/ER cells, while the EMT phenotype was promoted in APE1‐overexpressed HCC827 and PC‐9 cells. Furthermore, a specific APE1 redox inhibitor (ie, E3330) effectively reversed the EMT phenotype and further sensitized the cells to EGFR‐TKIs. Conclusion This study revealed a significant role of APE1 in EGFR‐TKI resistance via novel regulatory effects on the EMT phenotype in NSCLC.

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