Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors
Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors
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DOI：
10.1158/0008-5472.can-17-3146
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发表时间：
2018-06-15
期刊：
影响因子：
11.2
通讯作者：
Cho, Byoung Chul
中科院分区：
文献类型：
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作者：
Yun, Mi Ran;Lim, Sun Min;Cho, Byoung Chul
间变性淋巴瘤激酶(ALK)抑制剂对ALK融合阳性肺癌患者非常有效，但难免会出现获得性耐药。继发性突变的鉴定受到了相当大的关注，但大多数病例不能仅用遗传原因来解释，这增加了获得性耐药的表观遗传机制的可能性。在这里，我们研究了转录组和增强子景观在对ALK抑制剂的获得性耐药发展过程中的动态变化。在获得抗性的过程中，组蛋白H3赖氨酸27乙酰化(H3K27ac)发生了深刻的变化，增强子重塑诱导了miRNAs和mRNAs的表达变化。与AX1等靶基因激活相关的H3K27ac水平降低和miR-34a表达减少。泛组蛋白脱乙酰酶抑制剂Panobinostat改变了H3K27ac的轮廓，激活了肿瘤抑制基因miR-449，如miR-34家族的另一个成员miR-449，并与Al.K抑制剂协同诱导耐药细胞、异种移植瘤和EML4-ALK转基因小鼠的抗增殖作用。对ALK抑制剂治疗前后患者样本的配对分析表明，抑制miR-34a或miR-449a和激活Ax1是ALK继发突变的互斥。我们的发现表明增强子重塑和miRNAs的表达改变在癌症耐药中起关键作用，并提示针对表观遗传途径的策略是克服癌症治疗获得性耐药的潜在有效方法。意义：表观遗传去调节驱动ALK阳性肺癌对Al.K抑制剂的获得性耐药。(C)2018年AACR。
Anaplastic lymphoma kinase (ALK) inhibitors are h ighly 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 Al.K 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 mi R-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 Al.K inhibitors in ALK-positive lung cancer. (C) 2018 AACR.