Kaul Aparna, Toonen Joseph A, Cimino Patrick J, Gianino Scott M, Gutmann David H
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (A.K., J.A.T., S.M.G., D.H.G.); Department of Pathology, Washington University School of Medicine, St. Louis, Missouri (P.J.C.).
Neuro Oncol. 2015 Jun;17(6):843-53. doi: 10.1093/neuonc/nou329. Epub 2014 Dec 21.
Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth.
Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma-bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction.
Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma-associated retinal ganglion cell loss and nerve fiber layer thinning.
These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials.
1型神经纤维瘤病（NF1）患儿会发生视神经通路胶质瘤，这是由NF1蛋白对Ras活性的调节受损所致。实施生物靶向治疗的一个障碍是对下游Ras效应器（丝裂原活化蛋白激酶激酶[MEK]、Akt）对视神经胶质瘤维持的个体贡献了解不全面。本研究旨在探讨MEK和Akt信号传导对Nf1视神经胶质瘤生长的重要性。
采用原代新生小鼠星形胶质细胞培养来确定磷脂酰肌醇-3激酶（PI3K）/Akt和MEK抑制对Nf1缺陷型星形胶质细胞生长的影响。利用携带Nf1视神经胶质瘤的小鼠来评估Akt和MEK抑制对肿瘤体积、增殖及视网膜神经节细胞功能障碍的影响。
在体外Nf1缺陷型星形胶质细胞及体内Nf1小鼠视神经胶质瘤中，MEK和Akt均过度激活。药理学上抑制PI3K或Akt可将Nf1缺陷型星形胶质细胞增殖降低至野生型水平，而抑制PI3K可减小Nf1视神经胶质瘤体积并降低其增殖。抑制Akt对Nf1缺陷型星形胶质细胞和视神经胶质瘤生长的作用反映了Akt依赖性的雷帕霉素哺乳动物靶蛋白（mTOR）激活。持续的MEK药理学阻断也可减弱Nf1缺陷型星形胶质细胞以及Nf1视神经胶质瘤的体积和增殖。重要的是，这些MEK抑制作用是由p90RSK介导的、独立于Akt的mTOR激活所致。最后，抑制PI3K和MEK均可减少视神经胶质瘤相关的视网膜神经节细胞丢失及神经纤维层变薄。
这些发现表明，两条不同的Ras效应器途径在mTOR信号传导上的汇聚维持了Nf1小鼠视神经胶质瘤的生长，支持在未来人类NF1视神经通路胶质瘤临床试验中评估靶向mTOR功能的药理学抑制剂。
