EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.
EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.
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DOI：
10.1038/nature14122
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发表时间：
2015-04-09
期刊：
影响因子：
64.8
通讯作者：
Kim, Carla F.
中科院分区：
文献类型：
--
作者：
Fillmore, Christine M.;Xu, Chunxiao;Desai, Pooja T.;Berry, Joanne M.;Rowbotham, Samuel P.;Lin, Yi-Jang;Zhang, Haikuo;Marquez, Victor E.;Hammerman, Peter S.;Wong, Kwok-Kin;Kim, Carla F.
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因。化疗，如拓扑异构酶II抑制剂（TopoIII）依托泊苷有效地减少了少数NSCLC患者的疾病，因此，替代药物靶点，包括表观遗传酶，正在考虑进行治疗干预。一个有希望的潜在表观遗传靶标是甲基转移酶EZH2，其在多梳抑制复合物2（PRC2）的背景下众所周知在赖氨酸27（H3K27me3）处使组蛋白H3三甲基化并引发基因沉默。在这里，我们证明了EZH2抑制（EZH2i）在体外和体内对NSCLC的TopoIII反应具有不同的影响。EGFR和BRG1突变是预测EZH2i对TopoIII敏感性增强的遗传生物标志物。BRG 1功能缺失突变型肿瘤对EZH2i的反应是S期、后期桥接、凋亡和TopoIII敏感性增加。相反，EGFR和BRG1野生型肿瘤上调BRG1对EZH2i的反应，并最终变得对TopoIII更耐药。由于EGFR和BRG 1之间的遗传拮抗作用，EGFR功能获得性突变肿瘤对EZH2i和TopoIII双重治疗也敏感。这些发现表明，在遗传复杂的NSCLC疾病中进行精准医学是一个令人兴奋的机会。
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Chemotherapies such as the topoisomerase II inhibitor (TopoIIi) etoposide effectively reduce disease in a minority of NSCLC patients; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the Polycomb Repressive Complex 2 (PRC2) is well known to tri-methylate Histone H3 at lysine 27 (H3K27me3) and elicit gene silencing. Here, we demonstrate that EZH2 inhibition (EZH2i) had differential effects on TopoIIi response of NSCLCs in vitro and in vivo. EGFR and BRG1 mutations were genetic biomarkers that predicted enhanced sensitivity to TopoIIi in response to EZH2i. BRG1 loss-of-function mutant tumors responded to EZH2i with increased S phase, anaphase bridging, apoptosis, and TopoIIi sensitivity. Conversely, EGFR and BRG1 wild-type tumors up-regulated BRG1 in response to EZH2i and ultimately became more resistant to TopoIIi. EGFR gain-of-function mutant tumors were also sensitive to dual EZH2i and TopoIIi, due to genetic antagonism between EGFR and BRG1. These findings suggest an exciting opportunity for precision medicine in the genetically complex disease of NSCLC.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
3.9
作者：
Medina, Pedro P.;Romero, Octavio A.;Sanchez-Cespedes, Montse
通讯作者：
Sanchez-Cespedes, Montse
影响因子：
82.9
作者：
Beer, DG;Kardia, SLR;Hanash, S
通讯作者：
Hanash, S
影响因子：
4.4
作者：
Balko JM;Potti A;Saunders C;Stromberg A;Haura EB;Black EP
通讯作者：
Black EP