https://scholars.lib.ntu.edu.tw/handle/123456789/494914
標題: | Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors | 作者: | Yun M.R. Lim S.M. Kim S.-K. Choi H.M. Pyo K.-H. Kim S.K. Lee J.M. Lee Y.W. Choi J.W. Kim H.R. Hong M.H. Haam K. Huh N. Kim J.-H. Kim Y.S. Shim H.S. Soo R.A. JIN-YUAN SHIH Chih-Hsin CHIH-HSIN YANG Kim M. Cho B.C. |
公開日期: | 2018 | 出版社: | American Association for Cancer Research Inc. | 卷: | 78 | 期: | 12 | 起(迄)頁: | 3350-3362 | 來源出版物: | Cancer Research | 摘要: | Anaplastic 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 panhistone 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. ? 2018 AACR. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85048712195&doi=10.1158%2f0008-5472.CAN-17-3146&partnerID=40&md5=8cdb4b188524803643454168f68d2e6d https://scholars.lib.ntu.edu.tw/handle/123456789/494914 |
ISSN: | 0008-5472 | DOI: | 10.1158/0008-5472.CAN-17-3146 | SDG/關鍵字: | anaplastic lymphoma kinase inhibitor; ceritinib; histone H3; microRNA; microRNA 34a; microRNA 449a; panobinostat; transcriptome; unclassified drug; animal experiment; animal model; antiproliferative activity; Article; cancer resistance; cell proliferation; epigenetics; gene activation; gene expression; gene rearrangement; gene repression; histone acetylation; human; human cell; human tissue; in vivo study; lung cancer; mouse; nonhuman; priority journal; transcriptomics; transgenic mouse |
顯示於: | 腫瘤醫學研究所 |
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