Open AccessExosomes transmit T790M mutation‐induced resistance in EGFR‐mutant NSCLC by activating PI3K/AKT signalling pathway
Author(s) -
Liu Xiaozhen,
Jiang Tao,
Li Xuefei,
Zhao Chao,
Li Jiayu,
Zhou Fei,
Zhang Limin,
Zhao Sha,
Jia Yijun,
Shi Jinpeng,
Gao Guanghui,
Li Wei,
Zhao Jing,
Chen Xiaoxia,
Su Chunxia,
Ren Shengxiang,
Zhou Caicun
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14838
Subject(s) - t790m , microvesicles , gefitinib , pi3k/akt/mtor pathway , protein kinase b , biology , cancer research , small interfering rna , microrna , rna interference , cell culture , exosome , in vivo , microbiology and biotechnology , signal transduction , epidermal growth factor receptor , rna , transfection , gene , genetics , cancer
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.