Exosomes miR-184 and miR-3913-5p are involved in Osimertinib resistance in non-small cell lung cancer patients with exon 21 L858R mutation

Abstract Background The third-generation of EGFR-TKI Osimertinib has become an important treatment option for patients with EGFR-mutant advanced NSCLC. In recent years, more and more studies have begun to pay attention to the ability of miRNAs in exosomes secreted by tumor cells to transmit resistance information. The mechanisms of exosomal miRNAs involved in Osimertinib resistance need to be studied. Methods We constructed an Osimertinib-resistant cell line H1975-OR, and collected the exosomes from the cells of the drug-resistant strain and the sensitive strain, and extracted respective RNA for sequencing. We also compared miRNAs in serum exosomes of three patients before and after resistance to Osimertinib. Enlarged samples were then validated in 64 NSCLC patients. Results Cluster analysis of target genes revealed that miRNAs in exosomes participate in Osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality, PI3K pathway activation). MiR-184 and miR-3913-5p increased significantly in serum exosomes of patients with later Osimertinib resistance. These two miRNAs mainly cause EGFR resistance in two types of NSCLC patients, EGFR exon 21 L858R mutation and T790M positive. Conclusions Exosomes miR-184 and miR-3913-5p mainly cause Osimertinib resistance in lung cancer patients containing EGFR exon 21 L858R + and T790M + . They are regarded as important biomarkers of third-generation EGFR-TKI resistance. This not only enriches the application of liquid biopsy in lung cancer drug resistance, but also provides a direction for future targeted drug research.