{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:22:55Z","timestamp":1790810575772,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T00:00:00Z","timestamp":1547683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lee and the Ho Families Respiratory Research Fund","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers11010104","type":"journal-article","created":{"date-parts":[[2019,1,18]],"date-time":"2019-01-18T02:22:23Z","timestamp":1547778143000},"page":"104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Transfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6902-8402","authenticated-orcid":false,"given":"Hoi-Hin","family":"Kwok","sequence":"first","affiliation":[{"name":"Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7183-5281","authenticated-orcid":false,"given":"Ziyu","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peony Wing-Chi","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas Shek-Kong","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret Heung-Ling","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria Y.F.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Occupational Medicine, Epidemiology &amp; Prevention, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Great Neck, New York, NY 11021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Sau-Man","family":"Ip","sequence":"additional","affiliation":[{"name":"Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0004-2660","authenticated-orcid":false,"given":"David Chi-Leung","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e347","DOI":"10.1016\/S1470-2045(16)30123-1","article-title":"Novel therapeutic targets on the horizon for lung cancer","volume":"17","author":"Tan","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1158\/2159-8290.CD-16-0596","article-title":"Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer","volume":"6","author":"Gainor","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1056\/NEJMoa1616288","article-title":"Tracking the Evolution of Non\u2013Small-Cell Lung Cancer","volume":"376","author":"Wilson","year":"2017","journal-title":"New Engl. 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