Background
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. Recently, the drug resistance information transmitted by exosomal miRNAs has attracted much attention. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored.
Conclusions
The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.
Methods
We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The
Results
Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 and miR-3913-5p expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-3913-5p was associated with TNM stage, platelet count, tumor marker carcinoembryonic antigen, and distant metastases. In patients with EGFR exon 21 L858R mutation, the increased expression levels of miR-184 and miR-3913-5p derived from serum exosomes indicated osimertinib resistance. Similarly, for T790M-positive patients, the level of exosome-derived miR-3913-5p can be used as a predictive marker for osimertinib resistance. Conclusions: The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.