Abstract
Emerging evidence has shown that exosomes derived from drug‐resistant tumour cells are able to horizontally transmit drug‐resistant phenotype to sensitive cells. However, whether exosomes shed by EGFR T790M‐mutant–resistant NSCLC cells could transfer drug resistance to sensitive cells has not been investigated. We isolated exosomes from the conditioned medium (CM) of T790M‐mutant NSCLC cell line H1975 and sensitive cell line PC9. The role and mechanism of exosomes in regulating gefitinib resistance was investigated both in vitro and in vivo. Exosome‐derived miRNA expression profiles from PC9 and H1975 were analysed by small RNA sequencing and confirmed by qRT‐PCR. We found that exosomes shed by H1975 could transfer gefitinib resistance to PC9 both in vitro and in vivo through activating PI3K/AKT signalling pathway. Small RNA sequencing and RT‐PCR confirmed that miR‐3648 and miR‐522‐3p were the two most differentially expressed miRNAs and functional study showed that up‐regulation of miR‐522‐3p could induce gefitinib resistance in PC9 cell. The findings of our study reveal an important mechanism of acquired resistance to EGFR‐TKIs in NSCLC.
Highlights
With the tremendous development in understanding lung cancer biology, the treatment strategies for advanced lung cancer, especially non–small-cell lung cancer (NSCLC), have changed and currently are based on genetic abnormalities.[1,2,3] tremendous initial response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant advanced NSCLC patients, acquired resistance inevitably develops and T790M mutation accounts for 50%-60% resistant cases.[4,5,6] Researchers have reported that genetic tolerance might arise from small group of drug-resistant cells in patients.[7]
These results indicated that exosomes released by EGFR-TKI–resistant cell H1975 can inhibit the therapeutic effects of gefitinib and promote tumour growth in vivo
Our results indicated that exosomes derived from EGFR-TKI–resistant cell H1975 could induce gefitinib resistance in sensitive cell PC9 through activating PI3K/AKT signalling pathway
Summary
With the tremendous development in understanding lung cancer biology, the treatment strategies for advanced lung cancer, especially non–small-cell lung cancer (NSCLC), have changed and currently are based on genetic abnormalities.[1,2,3] tremendous initial response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant advanced NSCLC patients, acquired resistance inevitably develops and T790M mutation accounts for 50%-60% resistant cases.[4,5,6] Researchers have reported that genetic tolerance might arise from small group of drug-resistant cells in patients.[7]. In our study, we investigated the contributions of exosomes shed by EGFR-TKI–resistant NSCLC cells carrying T790M mutation to transferring drug resistance to sensitive cells and explored the potential mechanisms.
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