Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): QiWen Fan, Ozlem Aksoy, Robyn A. Wong, Shirin Ilkhanizadeh, Chris J. Novotny, William C. Gustafson, Albert Yi-Que Truong, Geraldine Cayanan, Erin F. Simonds, Daphne Haas-Kogan, Joanna J. Phillips, Theodore Nicolaides, Masanori Okaniwa, Kevan M. Shokat, William A. Weiss
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.
Teaser
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.http://ift.tt/2mn8FfY
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