A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

作者：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^*

来源：Cancer Cell, 2017, 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.

• 出版日期2017-3-13