Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation have an initial favorable clinical response to the tyrosine kinase inhibitors (TKIs). Unfortunately, rapid resistance occurs mainly because of genetic alterations, including amplification of the hepatocyte growth factor receptor (MET) and its abnormal activity. The RNA post-transcriptional modifications that contribute to aberrant expression of MET in cancer are largely under-investigated and among them is the adenosine-to-inosine (A-to-I) RNA editing of microRNAs. A reduction of A-to-I editing in position 5 of miR-411-5p has been identified in several cancers, including NSCLC. In this study, thanks to cancer-associated gene expression analysis, we assessed the effect of the edited miR-411-5p on NSCLC cell lines. We found that edited miR-411-5p directly targets MET and negatively affects the mitogen-activated protein kinases (MAPKs) pathway. Considering the predominant role of the MAPKs pathway on TKIs resistance, we generated NSCLC EGFR mutated cell lines resistant to TK inhibitors and evaluated the effect of edited miR-411-5p overexpression. We found that the edited miR-411-5p reduces proliferation and induces apoptosis, promoting EGFR TKIs response in NSCLC-resistant cells.
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The datasets generated and/or analyzed during the current study have been submitted to the GEO repository (accession # GSE221334).
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We thank the Virginia Commonwealth University Flow Cytometry Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059. We thank Dr. Theresa Swift-Scanlan for performing nCounter PanCancer Pathways Panel.
This work was supported by grants from the National Institutes of Health (NCI NCATS 5KL2TR002648), 1P20CA252717-01A1, and the American Lung Association (LCDA-922902).
The authors declare no competing interests.
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Romano, G., Le, P., Nigita, G. et al. A-to-I edited miR-411-5p targets MET and promotes TKI response in NSCLC-resistant cells. Oncogene 42, 1597–1606 (2023). https://doi.org/10.1038/s41388-023-02673-y