| Literature DB >> 28292440 |
QiWen Fan1, Ozlem Aksoy1, Robyn A Wong1, Shirin Ilkhanizadeh1, Chris J Novotny2, William C Gustafson3, Albert Yi-Que Truong4, Geraldine Cayanan1, Erin F Simonds1, Daphne Haas-Kogan5, Joanna J Phillips6, Theodore Nicolaides4, Masanori Okaniwa2, Kevan M Shokat2, William A Weiss7.
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.Entities:
Keywords: FKBP12, FK506 binding protein 12; FRB, FK506 rapamycin binding; GBM, glioblastoma; PI3K, phosphatidylinositol 3' kinase; TORKi, mTOR kinase inhibitor; mTOR mechanistic target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2
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Year: 2017 PMID： 28292440 PMCID： PMC5386178 DOI： 10.1016/j.ccell.2017.01.014
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743