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

TitleTransfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma
Authors
Keywordsextracellular vesicles
TKI-resistance
anaplastic lymphoma kinase
non-small cell lung cancer
intratumoural heterogeneity
Issue Date2019
PublisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/
Citation
Cancers, 2019, v. 11, p. article no. 104 How to Cite?
AbstractAnaplastic 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.
Persistent Identifierhttp://hdl.handle.net/10722/273929
ISSN
2017 Impact Factor: 5.326
2015 SCImago Journal Rankings: 1.630
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorKwok, HH-
dc.contributor.authorNING, Z-
dc.contributor.authorChong, PWC-
dc.contributor.authorWan, TSK-
dc.contributor.authorNg, MHL-
dc.contributor.authorHo, GYF-
dc.contributor.authorIp, MSM-
dc.contributor.authorLam, DCL-
dc.date.accessioned2019-08-18T14:51:32Z-
dc.date.available2019-08-18T14:51:32Z-
dc.date.issued2019-
dc.identifier.citationCancers, 2019, v. 11, p. article no. 104-
dc.identifier.issn2072-6694-
dc.identifier.urihttp://hdl.handle.net/10722/273929-
dc.description.abstractAnaplastic 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.-
dc.languageeng-
dc.publisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/-
dc.relation.ispartofCancers-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectextracellular vesicles-
dc.subjectTKI-resistance-
dc.subjectanaplastic lymphoma kinase-
dc.subjectnon-small cell lung cancer-
dc.subjectintratumoural heterogeneity-
dc.titleTransfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma-
dc.typeArticle-
dc.identifier.emailKwok, HH: kwokh@hku.hk-
dc.identifier.emailChong, PWC: peonyki@hku.hk-
dc.identifier.emailIp, MSM: msmip@hku.hk-
dc.identifier.emailLam, DCL: dcllam@hku.hk-
dc.identifier.authorityIp, MSM=rp00347-
dc.identifier.authorityLam, DCL=rp01345-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3390/cancers11010104-
dc.identifier.pmid30658414-
dc.identifier.pmcidPMC6356387-
dc.identifier.scopuseid_2-s2.0-85061906843-
dc.identifier.hkuros301595-
dc.identifier.volume11-
dc.identifier.spagearticle no. 104-
dc.identifier.epagearticle no. 104-
dc.publisher.placeSwitzerland-

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