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Cancer Res. 2018 Jun 15;78(12):3350-3362. doi: 10.1158/0008-5472.CAN-17-3146. Epub 2018 Apr 18.

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

Author information

1
JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.
2
Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
3
Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, Korea.
4
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
5
Department of Medical Science, Yonsei University College of Medicine, Seoul, Korea.
6
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
7
Department of Functional Genomics, University of Science and Technology, Daejeon, Korea.
8
Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
9
Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
10
Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore.
11
Graduate Institute of Oncology, National Taiwan University; and Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.
12
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. cbc1971@yuhs.ac mirang@kribb.re.kr.
13
JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea. cbc1971@yuhs.ac mirang@kribb.re.kr.
#
Contributed equally

Abstract

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 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. ©2018 AACR.

PMID:
29669761
DOI:
10.1158/0008-5472.CAN-17-3146
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