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Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors.

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dc.contributor.author김혜련-
dc.contributor.author심효섭-
dc.contributor.author조병철-
dc.contributor.author표경호-
dc.contributor.author홍민희-
dc.date.accessioned2018-11-16T16:41:16Z-
dc.date.available2018-11-16T16:41:16Z-
dc.date.issued2018-
dc.identifier.issn0008-5472-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/165223-
dc.description.abstractAnaplastic lymphoma kinase (ALK) inhibitors are highly effective in patients with ALK fusion-positive lung cancer, but acquired resistance invariably emerges. Identification of secondary mutations has received considerable attention, but most cases cannot be explained by genetic causes alone, raising the possibility of epigenetic mechanisms in acquired drug resistance. Here, we investigated the dynamic changes in the transcriptome and enhancer landscape during development of acquired resistance to ALK inhibitors. Histone H3 lysine 27 acetylation (H3K27ac) was profoundly altered during acquisition of resistance, and enhancer remodeling induced expression changes in both miRNAs and mRNAs. Decreased H3K27ac levels and reduced miR-34a expression associated with the activation of target genes such as AXL. Panobinostat, a pan-histone deacetylase inhibitor, altered the H3K27ac profile and activated tumor-suppressor miRNAs such as miR-449, another member of the miR-34 family, and synergistically induced antiproliferative effects with ALK inhibitors on resistant cells, xenografts, and EML4-ALK transgenic mice. Paired analysis of patient samples before and after treatment with ALK inhibitors revealed that repression of miR-34a or miR-449a and activation of AXL were mutually exclusive of secondary mutations in ALK. Our findings indicate that enhancer remodeling and altered expression of miRNAs play key roles in cancer drug resistance and suggest that strategies targeting epigenetic pathways represent a potentially effective method for overcoming acquired resistance to cancer therapy.Significance: Epigenetic deregulation drives acquired resistance to ALK inhibitors in ALK-positive lung cancer. Cancer Res; 78(12); 3350-62-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherAmerican Association for Cancer Research-
dc.relation.isPartOfCancer Research-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.titleEnhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors.-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학교실)-
dc.contributor.googleauthorMi Ran Yun-
dc.contributor.googleauthorSun Min Lim-
dc.contributor.googleauthorSeon-Kyu Kim-
dc.contributor.googleauthorHun Mi Choi-
dc.contributor.googleauthorKyoung-Ho Pyo-
dc.contributor.googleauthorSeong Keun Kim-
dc.contributor.googleauthorJi Min Lee-
dc.contributor.googleauthorYou Won Lee-
dc.contributor.googleauthorJae Woo Choi-
dc.contributor.googleauthorHye Ryun Kim-
dc.contributor.googleauthorMin Hee Hong-
dc.contributor.googleauthorKeeok Haam-
dc.contributor.googleauthorNanhyung Huh-
dc.contributor.googleauthorJong-Hwan Kim-
dc.contributor.googleauthorYong Sung Kim-
dc.contributor.googleauthorHyo Sup Shim-
dc.contributor.googleauthorRoss Andrew Soo-
dc.contributor.googleauthorJin-Yuan Shih-
dc.contributor.googleauthorJames Chih-Hsin Yang-
dc.contributor.googleauthorMirang Kim-
dc.contributor.googleauthorByoung Chul Cho-
dc.identifier.doi10.1158/0008-5472.CAN-17-3146-
dc.contributor.localIdA01166-
dc.contributor.localIdA01166-
dc.contributor.localIdA02219-
dc.contributor.localIdA03822-
dc.contributor.localIdA04809-
dc.contributor.localIdA04393-
dc.relation.journalcodeJ00452-
dc.identifier.eissn1538-7445-
dc.identifier.pmid29669761-
dc.identifier.urlhttp://cancerres.aacrjournals.org/content/78/12/3350.long-
dc.contributor.alternativeNameKim, Hye Ryun-
dc.contributor.alternativeNameShim, Hyo Sup-
dc.contributor.alternativeNameCho, Byoung Chul-
dc.contributor.alternativeNamePyo, Kyoung Ho-
dc.contributor.alternativeNameHong, Min Hee-
dc.contributor.affiliatedAuthor김혜련-
dc.contributor.affiliatedAuthor심효섭-
dc.contributor.affiliatedAuthor조병철-
dc.contributor.affiliatedAuthor표경호-
dc.contributor.affiliatedAuthor홍민희-
dc.citation.volume78-
dc.citation.number12-
dc.citation.startPage3350-
dc.citation.endPage3362-
dc.identifier.bibliographicCitationCancer Research, Vol.78(12) : 3350-3362, 2018-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers

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