期刊
BIOMEDICINES
卷 9, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/biomedicines9030243
关键词
extracellular vesicles; miRNA; EGFR mutation; heterogenous; NSCLC; EGFR-TKI
资金
- Ministry of Science and Technology, Taiwan [MOST 105-2314-B-006-076-MY2, MOST 107-2314-B-006-069, 108-2314-B-006-092-MY2]
- Center of Applied Nanomedicine, National Cheng Kung University from The Featured Areas Research Center Program
Intratumoral heterogeneity in EGFR-mutant NSCLC explains mixed responses to EGFR-TKIs. Analyses of EVs revealed that EV miRNAs can impact tumor cells' sensitivity to EGFR-TKIs, offering potential prognostic biomarkers for EGFR-mutant NSCLC.
Intratumoral heterogeneity in epidermal growth factor receptor (EGFR)-mutant mutant non-small-cell lung cancer (NSCLC) explains the mixed responses to EGFR-tyrosine kinase inhibitors (TKIs). However, some studies showed tumors with low abundances of EGFR mutation still respond to EGFR-TKI, and the mechanism remained undetermined. Extracellular vesicles (EVs) can transmit antiapoptotic signals between drug-resistant and drug-sensitive cells. Herein, we profiled EVs from EGFR-mutant cells to identify a novel mechanism explaining why heterogenous EGFR-mutant NSCLC patients still respond to EGFR-TKIs. We first demonstrated that the EVs from EGFR-mutant changes the wild-type cells' sensitivity to gefitinib by adding EV directly or coculturing EGFR wild-type (CL1-5) cells and EGFR-mutant (PC9) cells. In animal studies, only the combined treatment of PC9 EV and gefitinib delayed the tumor growth of CL1-5 cells. MicroRNA analysis comparing EV miRNAs from PC9 cells to those from CL1-5 cells showed that mir200 family members are most abundant in PC9 EVs. Furthermore, mir200a and mir200c were found upregulated in plasma EVs from good responders to EGFR-TKIs. Finally, the transfection of CL1-5 cells with miR200c inactivates downstream signaling pathways of EGFR, the EMT pathway, and enhances gefitinib sensitivity. Overall, our results suggest that in heterogeneous EGFR-mutant NSCLC, tumor cells transmit EV miRNAs that may affect sensitivity to EGFR-TKIs and provide potential prognostic biomarkers for EGFR-mutant NSCLC.
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