A-to-I edited miR-411-5p targets MET and promotes TKI response in NSCLC

Abstract

Abstract The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (TKR) frequently mutated in lung cancer. Despite initially favorable clinical responses of non-small cell lung cancer (NSCLC) patients harboring an EGFR mutation to treatment with tyrosine kinase inhibitors (TKIs), rapid resistance occurs mainly because of genetic alterations, including amplification of the hepatocyte growth factor receptor (MET). RNA post-transcriptional modifications that contribute to aberrant expression of MET in cancer are under-investigated. Among them, adenosine to inosine (A-to-I) RNA editing regulates RNA sequence, function, degradation, and structure. RNA editing has been observed in microRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional gene regulation. High throughput interrogation of the human genome allows for the identification of miRNA editing deregulation in cancer. However, the biological impact of edited miRNAs on lung cancer progression and drug resistance remains largely unknown. 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, we determined that edited miR-411-5p negatively affects the ERK1/2 pathway, directly targets MET, and promotes EGFR TKI response in NSCLC.