Exosomes Transmit T790M Mutation-induced Resistance in EGFR-mutant NSCLC by Activating PI3K/AKT Signalling Pathway

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2020 Jan 3

PMID 31894895

Citations 34

Authors

Xiaozhen Liu

Tao Jiang

Xuefei Li

Chao Zhao

Jiayu Li

Fei Zhou

Limin Zhang

Sha Zhao

Yijun Jia

Jinpeng Shi

Guanghui Gao

Wei Li

Jing Zhao

Xiaoxia Chen

Chunxia Su

Shengxiang Ren

Caicun Zhou

Affiliations

Soon will be listed here.

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.

Citing Articles

Exosomes-based liquid biopsy: An effective approach for drugs and therapeutics resistance screening in cancer.

Nyahatkar S, Kalele K J Liq Biopsy. 2025; 4:100144.

PMID: 40027144 PMC: 11863703. DOI: 10.1016/j.jlb.2024.100144.

Targeting the Tumor Microenvironment in EGFR-Mutant Lung Cancer: Opportunities and Challenges.

Lim J, Jung J, Kim Y, Kim C, Lee S, Park D Biomedicines. 2025; 13(2).

PMID: 40002883 PMC: 11852785. DOI: 10.3390/biomedicines13020470.

Peripheral Extracellular Vesicles for Diagnosis and Prognosis of Resectable Lung Cancer: The LUCEx Study Protocol.

Rodriguez-Sanz J, Munoz-Gonzalez N, Cubero J, Ordonez P, Gil V, Langarita R J Clin Med. 2025; 14(2).

PMID: 39860417 PMC: 11765880. DOI: 10.3390/jcm14020411.

Tumor-associated exosomes in cancer progression and therapeutic targets.

Liu X, Wu F, Pan W, Liu G, Zhang H, Yan D MedComm (2020). 2024; 5(9):e709.

PMID: 39247621 PMC: 11380050. DOI: 10.1002/mco2.709.

Unraveling the Connection: Extracellular Vesicles and Non-Small Cell Lung Cancer.

Wu J, Chen Y Int J Nanomedicine. 2024; 19:8139-8157.

PMID: 39139506 PMC: 11321355. DOI: 10.2147/IJN.S477851.

References

Thery C . Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep. 2011; 3:15. PMC: 3155154. DOI: 10.3410/B3-15. View

Yu H, Arcila M, Rekhtman N, Sima C, Zakowski M, Pao W . Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013; 19(8):2240-7. PMC: 3630270. DOI: 10.1158/1078-0432.CCR-12-2246. View

Zhou C, Wu Y, Chen G, Feng J, Liu X, Wang C . Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12(8):735-42. DOI: 10.1016/S1470-2045(11)70184-X. View

Colombo M, Raposo G, Thery C . Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014; 30:255-89. DOI: 10.1146/annurev-cellbio-101512-122326. View

Fumarola C, Bonelli M, Petronini P, Alfieri R . Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol. 2014; 90(3):197-207. DOI: 10.1016/j.bcp.2014.05.011. View

Qin X, Yu S, Zhou L, Shi M, Hu Y, Xu X . Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100-5p-dependent manner. Int J Nanomedicine. 2017; 12:3721-3733. PMC: 5439933. DOI: 10.2147/IJN.S131516. View

Mok T, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N . Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-57. DOI: 10.1056/NEJMoa0810699. View

El Andaloussi S, Mager I, Breakefield X, Wood M . Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013; 12(5):347-57. DOI: 10.1038/nrd3978. View

Wei F, Ma C, Zhou T, Dong X, Luo Q, Geng L . Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p. Mol Cancer. 2017; 16(1):132. PMC: 5526308. DOI: 10.1186/s12943-017-0694-8. View

10.

Ariyasu R, Nishikawa S, Uchibori K, Oh-Hara T, Yoshizawa T, Dotsu Y . High ratio of T790M to EGFR activating mutations correlate with the osimertinib response in non-small-cell lung cancer. Lung Cancer. 2018; 117:1-6. DOI: 10.1016/j.lungcan.2017.12.018. View

11.

Perez-Ramirez C, Canadas-Garre M, Molina M, Faus-Dader M, Angel Calleja-Hernandez M . PTEN and PI3K/AKT in non-small-cell lung cancer. Pharmacogenomics. 2015; 16(16):1843-62. DOI: 10.2217/pgs.15.122. View

12.

Frydrychowicz M, Kolecka-Bednarczyk A, Madejczyk M, Yasar S, Dworacki G . Exosomes - structure, biogenesis and biological role in non-small-cell lung cancer. Scand J Immunol. 2014; 81(1):2-10. DOI: 10.1111/sji.12247. View

13.

Yeung C, Co N, Tsuruga T, Yeung T, Kwan S, Leung C . Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016; 7:11150. PMC: 4820618. DOI: 10.1038/ncomms11150. View

14.

Herbst R, Morgensztern D, Boshoff C . The biology and management of non-small cell lung cancer. Nature. 2018; 553(7689):446-454. DOI: 10.1038/nature25183. View

15.

Chen W, Liu X, Lv M, Chen L, Zhao J, Zhong S . Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One. 2014; 9(4):e95240. PMC: 3989268. DOI: 10.1371/journal.pone.0095240. View

16.

Liu X, Jiang T, Li X, Zhao C, Li J, Zhou F . Exosomes transmit T790M mutation-induced resistance in EGFR-mutant NSCLC by activating PI3K/AKT signalling pathway. J Cell Mol Med. 2020; 24(2):1529-1540. PMC: 6991626. DOI: 10.1111/jcmm.14838. View

17.

Chabon J, Simmons A, Lovejoy A, Esfahani M, Newman A, Haringsma H . Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016; 7:11815. PMC: 4906406. DOI: 10.1038/ncomms11815. View

18.

Melo S, Sugimoto H, OConnell J, Kato N, Villanueva A, Vidal A . Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014; 26(5):707-21. PMC: 4254633. DOI: 10.1016/j.ccell.2014.09.005. View

19.

To K . MicroRNA: a prognostic biomarker and a possible druggable target for circumventing multidrug resistance in cancer chemotherapy. J Biomed Sci. 2013; 20:99. PMC: 3878201. DOI: 10.1186/1423-0127-20-99. View

20.

Wang J, Hendrix A, Hernot S, Lemaire M, de Bruyne E, Van Valckenborgh E . Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood. 2014; 124(4):555-66. DOI: 10.1182/blood-2014-03-562439. View