Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies
Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies
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DOI：
10.1093/neuonc/nor035
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发表时间：
2011-06-01
期刊：
影响因子：
15.9
通讯作者：
Reilly, Karlyne M.
中科院分区：
文献类型：
--
作者：
Guersel, Demirkan B.;Connell-Albert, Yvette S.;Reilly, Karlyne M.
越来越多的研究表明，星形细胞瘤和多形性胶质母细胞瘤需要精心定制的分子靶向治疗才能成功治疗。最近对胶质母细胞瘤中突变和基因表达变化的综合鉴定表明，NF1突变是人类胶质母细胞瘤中常见的改变。我们已经开发了14个肿瘤系，从H级到IV级星形细胞瘤，从我们的Nf1-/+发展；Trp53-/+ cis小鼠模型，并使用该面板表征星形细胞瘤和胶质母细胞瘤候选治疗靶点的信号转导途径和抑制剂。我们发现这些肿瘤不同程度地表达血小板源性生长因子受体- α、表皮生长因子受体及其各自的配体。我们发现表皮生长因子受体和血小板源性生长因子受体α下游的MEK和PI3K信号通路是星形细胞瘤细胞充分增殖所必需的；然而，在阻断细胞生长方面，抑制PI3K通路比抑制MEK更有效。我们研究了PI3K/Akt/mTOR信号通路的抑制剂，发现PI-103和TCN对Nf1和TrpS3突变型星形细胞瘤细胞的生长有特别的抑制作用。
A growing body of work suggests that astrocytomas and glioblastoma multiforme will require carefully tailored, molecularly targeted therapy for successful treatment. Recent efforts to comprehensively identify mutations and gene expression changes in glioblastoma have shown that mutation of NF1 is a common alteration in human glioblastoma. We have developed and characterized a panel of 14 tumor lines from grades H through IV astrocytomas developed from our Nf1-/+; Trp53-/+ cis mouse model and have used this panel to characterize signal transduction pathways and inhibitors that are candidate therapeutic targets for astrocytoma and glioblastoma. We show that these tumors express platelet-derived growth factor receptor-alpha, epidermal growth factor receptor, and their respective ligands to-varying degrees. We find that both the MEK and PI3K signaling pathways downstream of epidermal growth factor receptor and platelet-derived growth factor receptor-alpha are necessary for full proliferation of astrocytoma cells; however, inhibition of the PI3K pathway is more effective than inhibition of MEK at blocking cell growth. We have examined inhibitors of the PI3K/Akt/mTOR signaling pathway and find that PI-103 and TCN show particular promise for inhibiting growth in Nf1 and TrpS3 mutant astrocytoma cells.