Abstract LB-400: STAT3 mediates resistance to MEK inhibitor through microRNA miR-17
Abstract LB-400: STAT3 mediates resistance to MEK inhibitor through microRNA miR-17
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DOI：
10.1158/1538-7445.am2011-lb-400
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发表时间：
2011-04
期刊：
影响因子：
11.2
通讯作者：
B. Dai;J. Meng;M. Peyton;L. Girard;W. Bornmann;L. Ji;J. Minna;B. Fang;J. Roth
中科院分区：
文献类型：
--
作者：
B. Dai;J. Meng;M. Peyton;L. Girard;W. Bornmann;L. Ji;J. Minna;B. Fang;J. Roth
AZD 6244是一种靶向MEK通路的小分子抑制剂，目前正在进行临床试验。然而，介导对MEK抑制的内在抗性的机制仍有待完全表征。为了确定MEK抑制剂耐药的分子机制，我们分析了AZD 6244治疗后38种肺癌细胞系的反应及其全基因组基因表达谱，并确定了一组与AZD 6244治疗敏感性或耐药性相关的基因。免疫抑制通路分析显示，信号转导和转录激活因子3（STAT 3）通路的激活与MEK抑制剂耐药相关。使用STAT 3特异性抑制剂JSI-124抑制STAT 3通路，可使肺癌细胞对AZD 6244治疗敏感，并在体外和体内诱导凋亡。此外，STAT 3抑制剂与AZD 6244联合诱导了BIM的表达和聚（ADP-核糖）聚合酶（PARP）切割，而STAT 3途径的激活抑制了BIM的表达，从而诱导了MEK抑制剂的耐药性。此外，我们还发现，受STAT 3调控的miR-17通过靶向BIM在STAT 3介导的MEK抑制剂耐药性中发挥重要作用。用抗miR-17抑制miR-17通过诱导BIM和PARP裂解使耐药细胞对AZD 6244敏感。我们得出结论，STAT 3介导的miR-17过表达阻断了BIM表达，导致对AZD 6244的耐药性。这些结果暗示了通过将AZD 6244与STAT 3抑制剂或miR-17抑制剂组合来克服MEK抑制剂抗性的新的替代方法。引用格式：{Authors}。【摘要】【摘要】于：美国癌症研究协会第102届年会论文集; 2011年4月2日至6日;奥兰多，佛罗里达州费城（PA）：AACR;癌症研究2011年;71（8增刊）：摘要编号LB-400。doi：10.1158/1538-7445.AM2011-LB-400
AZD6244 is a small-molecule-based inhibitor targeting the MEK pathway that is currently in clinical trials. However, the mechanisms mediating intrinsic resistance to MEK inhibition remain to be completely characterized. To identify the molecular mechanism of MEK inhibitor resistance, we analyzed responses of 38 lung cancer cell lines following AZD6244 treatment and their genome-wide gene expression profiles and identified a panel of genes correlated with sensitivity or resistance to AZD6244 treatment. Ingenuity pathway analysis revealed that activation of the signal transducer and activator of transcription 3 (STAT3) pathway was associated with MEK inhibitor resistance. Inhibition of the STAT3 pathway using JSI-124, a STAT3-specific inhibitor, sensitized lung cancer cells to AZD6244 treatment and induced apoptosis in vitro and in vivo. Moreover, combining a STAT3 inhibitor with AZD6244 induced the expression of BIM and poly (ADP-ribose) polymerase (PARP) cleavage, whereas activation of the STAT3 pathway inhibited BIM expression and thus induced MEK inhibitor resistance. In addition, we found that miR-17, which is regulated by STAT3, played an important role in STAT3-mediated MEK inhibitor resistance by targeting BIM. Inhibition of miR-17 with anti-miR-17 sensitized resistant cells to AZD6244 by inducing BIM and PARP cleavage. We conclude that STAT3-mediated overexpression of miR-17 blocked BIM expression, which resulted in resistance to AZD6244. These results implicate novel alternative approaches for overcoming the MEK inhibitor resistance by combining AZD6244 with STAT3 inhibitors or miR-17 antagomirs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-400. doi:10.1158/1538-7445.AM2011-LB-400