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Cancers 2019, 11(1), 104; https://doi.org/10.3390/cancers11010104

Transfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma

1
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
2
Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
3
Department of Occupational Medicine, Epidemiology & Prevention, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Great Neck, New York, NY 11021, USA
*
Author to whom correspondence should be addressed.
Received: 11 December 2018 / Revised: 11 January 2019 / Accepted: 14 January 2019 / Published: 17 January 2019
(This article belongs to the Special Issue Molecular Profiling of Lung Cancer)
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Abstract

Anaplastic lymphoma kinase (ALK) translocation is an actionable mutation in lung adenocarcinoma. Nonetheless tumour consists of heterogeneous cell subpopulations with diverse phenotypes and genotypes, and cancer cells can actively release extracellular vesicles (EVs) to modulate the phenotype of other cells in the tumour microenvironment. We hypothesized that EVs derived from a drug-resistant subpopulation of cells could induce drug resistance in recipient cells. We have established ALK-translocated lung adenocarcinoma cell lines and subclones. The subclones have been characterized and the expression of EV-RNAs determined by quantitative polymerase chain reaction. The effects of EV transfer on drug resistance were examined in vitro. Serum EV-RNA was assayed serially in two patients prescribed ALK-tyrosine kinase inhibitor (ALK-TKI) treatment. We demonstrated that the EVs from an ALK-TKI-resistant subclone could induce drug resistance in the originally sensitive subclone. EV-RNA profiling revealed that miRNAs miR-21-5p and miR-486-3p, and lncRNAs MEG3 and XIST were differentially expressed in the EVs secreted by the resistant subclones. These circulating EV-RNA levels have been found to correlate with disease progression of EML4-ALK-translocated lung adenocarcinoma in patients prescribed ALK-TKI treatment. The results from this study suggest that EVs released by a drug-resistant subpopulation can induce drug resistance in other subpopulations and may sustain intratumoural heterogeneity. View Full-Text
Keywords: extracellular vesicles; TKI-resistance; anaplastic lymphoma kinase; non-small cell lung cancer; intratumoural heterogeneity extracellular vesicles; TKI-resistance; anaplastic lymphoma kinase; non-small cell lung cancer; intratumoural heterogeneity
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Kwok, H.-H.; Ning, Z.; Chong, P. .-C.; Wan, T. .-K.; Ng, M. .-L.; Ho, G.Y.; Ip, M. .-M.; Lam, D. .-L. Transfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma. Cancers 2019, 11, 104.

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