Journal
PHARMACOLOGICAL RESEARCH
Volume 165, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2021.105442
Keywords
NSCLC; T790M; miR-7; Exosomes; Gefitinib; YAP
Categories
Funding
- Natural Science Foundation of China [81774291]
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miR-7 plays a significant role in gefitinib resistance mechanism, it can be transferred via exosomes to reverse resistance and is associated with survival outcomes.
Epidermal growth factor receptor (EGFR) T790M mutation act as the dominant resistance mechanism to first and second generations tyrosine kinase inhibitors (TKIs), the roles of miR-7 in the development of T790M mutation are largely unknown. Here, we confirmed that the level of miR-7 was significantly higher in the gefitinib sensitivity PC9 cells compared to gefitinib resistance H1975 cells, and miR-7 overexpression promoted the apoptosis of H1975 cells by gefitinib treatment. Furthermore, we found that exosomes could transfer miR-7 mimics from PC9 cells to H1975 cells, which reversed gefitinib resistance through binding to YAP, and altered H1975 cells resistance phenotype in vitro. In addition, we suppressed exosomal miR-7 by GW4869, increasing PC9 cells chemoresistance to gefitinib treatment in vivo. Of note, we detected that miR-7 was significantly higher in serum exosomes from healthy controls than from patients with lung carcinoma, and high miR-7 expression was associated with strong response to lung carcinoma patients receiving gefitinib treatment, as well as a longer survival. Therefore, exosomal miR-7 can act as a potential biomarker and therapeutic target for EGFR T79M resistance mutations.
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