Abstract
BackgroundEpithelial‐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.MethodsThe 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.ResultsWe 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.ConclusionThis study revealed a significant role of APE1 in EGFR‐TKI resistance via novel regulatory effects on the EMT phenotype in NSCLC.
Highlights
The introduction of EGFR tyrosine kinase inhibitors (EGFR- TKIs), including gefitinib, erlotinib, and icotinib,[1] has successfully improved the response rate, progression-free survival, and overall survival of advanced non-small-cell lung cancer (NSCLC) patients from
transforming growth factor-β (TGF-β) signaling plays a core regulatory role in the Epithelial-to-mesenchymal transition (EMT) process, and we previously demonstrated that apyrimidinic endonuclease 1 (APE1) promotes TGF-β transcription in osteosarcoma, a malignancy derived from mesenchymal tissue.[9]
Considering APE1 expression is not affected by E3330/Icotinib combinational treatment, these results provide support for the hypothesis that the redox activity of APE1 is critical for EMT in EGFR-TKI-resistant NSCLC cells
Summary
This work was supported by grants from the National Natural Science Foundation of China (NSFC) No 81501976 to Y.P. and No 81673029 to M. L. This work was supported by the Associazione Italiana Ricerca sul Cancro-AIRC [IG2013-14038 and IG2016-18400 to G.T.].
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