miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells

Abstract

Nintedanib (BIBF1120) is a multi-targeted angiokinase inhibitor and has been evaluated in idiopathic pulmonary fibrosis and advanced non-small cell lung cancer (NSCLC) patients in clinical studies. In the present study, we evaluated the antitumor effects of nintedanib in 16 NSCLC cell lines and tried to identify microRNA (miRNA) associated with sensitivity to nintedanib. No correlations between FGFR, PDGFR and VEGFR family activation and sensitivity to nintedanib were found. The difference in miRNA expression profiles between 5 nintedanib-sensitive and 5 nintedanib-resistant cell lines was evaluated by miRNA array and quantitative RT-PCR analysis (qRT-PCR). Expression of miR-200b, miR-200a and miR-141 belonging to the miR-200 family which contributes to epithelial-mesenchymal transition (EMT), was significantly lower in 5 nintedanib-resistant than in 5 nintedanib-sensitive cell lines. We examined the protein expression of EMT markers in these 10 NSCLC cell lines. E-cadherin expression was lower, and vimentin and ZEB1 expression were higher in 5 nintedanib-resistant cell lines. PC-1 was the most sensitive of the NSCLC cell lines to nintedanib. We established nintedanib-resistant PC-1 cells (PC-1R) by the stepwise method. PC-1R cells also showed decreased expression of miR-200b, miR-141 and miR-429 and increased expression of ZEB1 and ZEB2. We confirmed that induction of miR-200b or miR-141 enhanced sensitivity to nintedanib in nintedanib-resistant A549 and PC1-R cells. In addition, we evaluated the response to gefitinib in combination with nintedanib after TGF-β1 exposure of A549 cells. Nintedanib was able to reverse TGF-β1-induced EMT and resistance to gefitinib caused by miR-200b and miR-141 upregulation and ZEB1 downregulation. These results suggested that the miR-200/ZEB axis might be predictive biomarkers for sensitivity to nintedanib in NSCLC cells. Furthermore, nintedanib combined with gefitinib might be a novel therapeutic strategy for NSCLC cells with EMT phenotype and resistance to gefitinib.

A nine-miRNA signature as a potential diagnostic marker for breast carcinoma: An integrated study of 1,110 cases

“…These discrepancies may be partially explained by the various sources of the cases studied, different detection techniques and different platforms used. It is reported that members of the miR-200 family can reverse epithelial-mesenchymal transition (EMT) by increasing E-cadherin expression and decreasing ZEB1, ZEB2 and β-catenin expression, further inhibiting cancer cell invasion and migration (31,(37)(38)(39)(40). Notably, EMT mechanisms are distinct in various malignancies, and the expression of EMT markers (E-cadherin and ZEB) is inconsistent in diverse types of cancers and different histological types of the same cancer (41).…”

miR‐339‐5p downregulation contributes to Taxol resistance in small‐cell lung cancer by targeting α1,2‐fucosyltransferase 1

“…MiRNAs have been demonstrated to be differently expressed between normal and cancer cells, and aberrant expression of miRNAs has a key association with the development, invasion, metastasis, and prognosis of NSCLC. In addition, miRNAs modulate cancer therapy response and resistance ; however, limited evidence has been obtained for miRNA‐mediated signaling networks that regulate progression and chemoresistance in NSCLC.…”

Impact of Epidermal Growth Factor Receptor Mutation on Clinical Outcomes of Nintedanib Plus Docetaxel in Patients with Previously Treated Non-Small Cell Lung Cancer from the Korean Named Patient Program

“…The antitumor effects of nintedanib on EGFR mutant lung cancer are expected to be mediated by the angiogenesis pathway and nintedanib target pathways, such as fibroblast growth factor receptor, Src. A recent preclinical study demonstrated that nintedanib restores EGFR-TKI sensitivity by reversing TGF-B1-induced EMT via miR-200b and miR-141 upregulation and ZEB1 downregulation [15].…”