Fan QiWen, Aksoy Ozlem, Wong Robyn A, Ilkhanizadeh Shirin, Novotny Chris J, Gustafson William C, Truong Albert Yi-Que, Cayanan Geraldine, Simonds Erin F, Haas-Kogan Daphne, Phillips Joanna J, Nicolaides Theodore, Okaniwa Masanori, Shokat Kevan M, Weiss William A
Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Cancer Cell. 2017 Mar 13;31(3):424-435. doi: 10.1016/j.ccell.2017.01.014.
Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (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 with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with 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.
尽管在高级别脑胶质瘤中，磷脂酰肌醇3激酶（PI3K）和AKT向雷帕霉素作用机制靶点（mTOR）的信号传导明显失调，但PI3K或AKT的阻断对胶质瘤中mTOR的下游活性影响极小。与mTOR激酶抑制剂（TORKi）相比，变构mTOR抑制剂（如雷帕霉素）对mTORC1的阻断不完全。在此，我们将与雷帕霉素相连的TORKi RapaLink-1与早期的mTOR抑制剂进行了比较。与雷帕霉素和RapaLink-1相比，TORKi的持久性较差。RapaLink-1与FKBP12（一种丰富的与mTOR相互作用的蛋白）结合，使得RapaLink-1得以积累。RapaLink-1显示出比雷帕霉素或TORKi更好的疗效，能有效阻断源自癌症的mTOR激活突变体。我们的研究重新确立了mTOR作为胶质瘤核心靶点的地位，并指出现有药物未能完全/持久抑制mTORC1的原因。
