Sensitivity of Glioblastomas to Clinically Available MEK Inhibitors Is Defined by Neurofibromin 1 Deficiency
Sensitivity of Glioblastomas to Clinically Available MEK Inhibitors Is Defined by Neurofibromin 1 Deficiency
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DOI：
10.1158/0008-5472.can-12-0334
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Pieper, Russell O.
中科院分区：
文献类型：
--
作者：
See, Wendy L.;Tan, I-Li;Pieper, Russell O.
神经纤维蛋白1（NF 1）的缺失导致RAS的过度活化，其进而通过RAF/MEK/ERK和磷酸肌醇3-激酶（PI 3 K）/mTOR途径发出信号以调节细胞生长和存活。由于NF 1缺陷型急性髓性白血病对MEK抑制剂敏感，我们在此研究了NF 1缺陷型多形性胶质母细胞瘤（GBM）是否对MEK抑制剂有反应。在19个GBM细胞系中，我们发现用临床上可用的MEK抑制剂PD 0325901或AZD 6244治疗降低了磷酸化ERK的水平，磷酸化ERK是MEK的下游效应物，而与NF 1状态无关。然而，生长抑制只发生在NF 1缺陷细胞的一个亚群中，与细胞周期蛋白D1水平降低、p27水平升高和G（1）阻滞相关。作为单一药物，PD 0325901也抑制了体内NF 1缺陷的MEK受体敏感细胞的生长。从机制上讲，NF 1缺陷的MEK受体敏感细胞依赖于RAF/MEK/ERK途径生长，并且不激活PI 3 K途径作为获得性抗性的机制。重要的是，通过添加双重PI 3 K/mTOR抑制剂PI-103，对MEK抑制具有内在抗性的NF 1缺陷细胞被敏化。综上所述，我们的研究结果表明，NF 1缺陷GBM的一个子集可能对目前正在临床试验中测试的MEK抑制剂有反应。Cancer Res; 72（13）; 3350-9. (C)2012年AACR。
Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G(1) arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor-sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor-sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials. Cancer Res; 72(13); 3350-9. (C) 2012 AACR.