EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition
EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition
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DOI：
10.1158/0008-5472.can-12-3479
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发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
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作者：
Nakagawa, Takayuki;Takeuchi, Shinji;Yano, Seiji
BIM (BCL2L11) 是 Bcl-2 蛋白家族中仅 BH3 的促凋亡成员。在 EGFR 突变形式的非小细胞肺癌 (NSCLC) 中，BIM 上调是 EGF 受体 (EGFR) 酪氨酸激酶抑制剂 (EGFR-TKI) 诱导细胞凋亡所必需的。值得注意的是，BIM 缺失多态性在 12.9% 的东亚个体中自然发生，损害了 EGFR-TKI 吉非替尼和厄洛替尼所需的促凋亡亚型的产生，因此赋予了固有的耐药表型。事实上，携带这种宿主 BIM 多态性的 NSCLC 患者对 EGFR-TKI 治疗的反应明显低于缺乏这种多态性的个体。为了纠正耐药组中的这种反应缺陷，我们研究了组蛋白脱乙酰酶 (HDAC) 抑制剂伏立诺他是否可以规避也具有 BIM 多态性的 EGFR 突变 NSCLC 细胞系中的 EGFR-TKI 耐药性。与我们的临床观察一致，我们发现此类细胞对吉非替尼诱导的细胞凋亡的敏感性远低于不具有多态性的 EGFR 突变细胞。值得注意的是，伏立诺他以剂量依赖性方式增加含有促凋亡 BH3 结构域的 BIM 亚型的表达，这足以恢复 EGFR 突变体、EGFR-TKI 耐药细胞中吉非替尼的死亡敏感性。在异种移植模型中，虽然吉非替尼通过不具有 BIM 多态性的肿瘤细胞凋亡诱导显着消退，但需要其与伏立诺他组合才能以相同的方式诱导具有 BIM 多态性的肿瘤显着消退。总之，我们的结果表明，在 EGFR 突变 NSCLC 病例中，HDAC 抑制如何能够表观遗传学恢复 BIM 功能和 EGFR-TKI 的死亡敏感性，其中对 EGFR-TKI 的耐药性与常见的 BIM 多态性相关。癌症研究； 73（8）； 2428-34。 (C) 2013 年 AACR。
BIM (BCL2L11) is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGF receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in EGFR-mutant forms of non-small cell lung cancer (NSCLC). Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKIs gefitinib and erlotinib and therefore conferring an inherent drug-resistant phenotype. Indeed, patients with NSCLC, who harbored this host BIM polymorphism, exhibited significantly inferior responses to EGFR-TKI treatment than individuals lacking this polymorphism. In an attempt to correct this response defect in the resistant group, we investigated whether the histone deacetylase (HDAC) inhibitor vorinostat could circumvent EGFR-TKI resistance in EGFR-mutant NSCLC cell lines that also harbored the BIM polymorphism. Consistent with our clinical observations, we found that such cells were much less sensitive to gefitinib-induced apoptosis than EGFR-mutant cells, which did not harbor the polymorphism. Notably, vorinostat increased expression in a dose-dependent manner of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the EGFR mutant, EGFR-TKI-resistant cells. In xenograft models, while gefitinib induced marked regression via apoptosis of tumors without the BIM polymorphism, its combination with vorinostat was needed to induce marked regression of tumors with the BIM polymorphism in the same manner. Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of EGFR-mutant NSCLC where resistance to EGFR-TKI is associated with a common BIM polymorphism. Cancer Res; 73(8); 2428-34. (C) 2013 AACR.