Abstract：
: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.
journal_name
Cancer Celljournal_title
Cancer cellauthors
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 WAdoi
10.1016/j.ccell.2017.01.014subject
Has Abstractpub_date
2017-03-13 00:00:00pages
424-435issue
3eissn
1535-6108issn
1878-3686pii
S1535-6108(17)30014-4journal_volume
31pub_type
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