A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.
A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.
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DOI：
10.1016/j.ccell.2017.01.014
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发表时间：
2017-03-13
期刊：
影响因子：
50.3
通讯作者：
Weiss WA
中科院分区：
文献类型：
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作者：
Fan Q;Aksoy O;Wong RA;Ilkhanizadeh S;Novotny CJ;Gustafson WC;Truong AY;Cayanan G;Simonds EF;Haas-Kogan D;Phillips JJ;Nicolaides T;Okaniwa M;Shokat KM;Weiss WA
尽管PI 3 K和AKT到mTOR的信号传导在高级别胶质脑肿瘤中显著失调，但阻断PI 3 K或AKT对胶质瘤中下游mTOR活性的影响最小。与mTOR激酶抑制剂（TORKi）相比，别构mTOR抑制剂（如雷帕霉素）不完全阻断mTORC 1。在这里，我们比较了RapaLink-1，一种与雷帕霉素相关的TORKi，与早期的mTOR抑制剂。与雷帕霉素和Rapalink-1相比，TORKi显示出较差的耐久性。RapaLink-1与FKBP 12相关，FKBP 12是一种丰富的mTOR相互作用蛋白，能够积累RapaLink-1。RapaLink-1显示出比雷帕霉素或TORKi更好的功效，有效地阻断癌症衍生的mTOR激活突变体。我们的研究重新确立了mTOR作为神经胶质瘤的中心靶点，并追踪了现有药物对mTORC 1的不完全/非持久抑制的失败。Fan等人用RapaLink-1靶向胶质母细胞瘤（GBM）中的mTORC 1活性，RapaLink-1由连接至mTOR激酶抑制剂的雷帕霉素组成。RapaLink-1降低mTORC 1在大脑中的活性，并抑制GBM异种移植物和脑癌基因工程小鼠模型的生长。
Although signaling from PI3K and AKT to mTOR is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared to mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier generation mTOR inhibitors. Compared to rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1. Fan et al. target mTORC1 activity in glioblastoma (GBM) with RapaLink-1, which is comprised of rapamycin linked to an mTOR kinase inhibitor. RapaLink-1 decreases mTORC1 activity in the brain and suppresses the growth of GBM xenografts and a genetically-engineered mouse model of brain cancer in vivo.