STAT3 Mediates Resistance to MEK Inhibitor through MicroRNA miR-17
STAT3 Mediates Resistance to MEK Inhibitor through MicroRNA miR-17
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DOI：
10.1158/0008-5472.can-10-3647
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发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Roth, Jack A.
中科院分区：
文献类型：
--
作者：
Dai, Bingbing;Meng, Jieru;Roth, Jack A.
AZD 6244是一种MEK（MAP/ERK激酶）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尚未完全表征。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。特别是，独创性途径分析揭示了STAT 3途径的激活与MEK抑制剂抗性相关。通过STAT 3特异性小分子抑制剂JSI-124或STAT 3特异性siRNA抑制该途径可使肺癌细胞对AZD 6244敏感并诱导凋亡。此外，将STAT 3抑制剂与AZD 6244组合诱导BIM和PARP裂解的表达，而STAT 3途径的激活抑制BIM表达并引起对MEK抑制剂的抗性。我们发现，STAT 3调节的microRNA miR-17在MEK抑制剂耐药中起着关键作用，因此miR-17抑制通过诱导BIM和PARP裂解使耐药细胞对AZD 6244敏感。总之，这些结果表明，STAT 3介导的miR-17过表达阻断了BIM表达，并导致对AZD 6244的耐药性。我们的研究结果提出了通过将AZD 6244与STAT 3或miR-17抑制剂组合来克服对MEK抑制剂的耐药性的新方法。Cancer Res; 71（10）; 3658-68. (C)2011年AACR。
AZD6244 is a small molecule inhibitor of the MEK (MAP/ERK kinase) pathway currently in clinical trials. However, the mechanisms mediating intrinsic resistance to MEK inhibition are not fully characterized. To define molecular mechanisms 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. In particular, ingenuity pathway analysis revealed that activation of the STAT3 pathway was associated with MEK inhibitor resistance. Inhibition of this pathway by JSI-124, a STAT3-specific small molecule inhibitor, or with STAT3-specific siRNA sensitized lung cancer cells to AZD6244 and induced apoptosis. Moreover, combining a STAT3 inhibitor with AZD6244 induced expression of BIM and PARP cleavage, whereas activation of the STAT3 pathway inhibited BIM expression and elicited resistance to MEK inhibitors. We found that the STAT3-regulated microRNA miR-17 played a critical role in MEK inhibitor resistance, such that miR-17 inhibition sensitized resistant cells to AZD6244 by inducing BIM and PARP cleavage. Together, these results indicated that STAT3-mediated overexpression of miR-17 blocked BIM expression and caused resistance to AZD6244. Our findings suggest novel approaches to overcome resistance to MEK inhibitors by combining AZD6244 with STAT3 or miR-17 inhibitors. Cancer Res; 71(10); 3658-68. (C) 2011 AACR.