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

 Mi Ran Yun  ;  Sun Min Lim  ;  Seon-Kyu Kim  ;  Hun Mi Choi  ;  Kyoung-Ho Pyo  ;  Seong Keun Kim  ;  Ji Min Lee  ;  You Won Lee  ;  Jae Woo Choi  ;  Hye Ryun Kim  ;  Min Hee Hong  ;  Keeok Haam  ;  Nanhyung Huh  ;  Jong-Hwan Kim  ;  Yong Sung Kim  ;  Hyo Sup Shim  ;  Ross Andrew Soo  ;  Jin-Yuan Shih  ;  James Chih-Hsin Yang  ;  Mirang Kim  ;  Byoung Chul Cho 
 Cancer Research, Vol.78(12) : 3350-3362, 2018 
Journal Title
 Cancer Research 
Issue Date
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
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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
Yonsei Authors
김혜련(Kim, Hye Ryun) ORCID logo https://orcid.org/0000-0002-1842-9070
심효섭(Shim, Hyo Sup) ORCID logo https://orcid.org/0000-0002-5718-3624
조병철(Cho, Byoung Chul) ORCID logo https://orcid.org/0000-0002-5562-270X
표경호(Pyo, Kyoung Ho) ORCID logo https://orcid.org/0000-0001-5428-0288
홍민희(Hong, Min Hee) ORCID logo https://orcid.org/0000-0003-3490-2195
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