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Elevated exosome-derived miRNAs predict osimertinib resistance in non-small cell lung cancer

Authors :
Xinying Li
Cen Chen
Zimu Wang
Jiaxin Liu
Wei Sun
Kaikai Shen
Yanling Lv
Suhua Zhu
Ping Zhan
Tangfeng Lv
Yong Song
Source :
Cancer Cell International, Vol 21, Iss 1, Pp 1-14 (2021)
Publication Year :
2021
Publisher :
BMC, 2021.

Abstract

Abstract 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. 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 were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients. 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. Graphic Abstract

Details

Language :
English
ISSN :
14752867
Volume :
21
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cancer Cell International
Publication Type :
Academic Journal
Accession number :
edsdoj.0da39f887d34806be06e29cc74dc6c9
Document Type :
article
Full Text :
https://doi.org/10.1186/s12935-021-02075-8