A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.

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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 31 Issue 3 Pg. 424-435 (03 13 2017) ISSN: 1878-3686 [Electronic] United States
• PMID: 28292440 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Multiprotein Complexes
• Protein Kinase Inhibitors
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Tacrolimus Binding Protein 1A
• Sirolimus

Topics

• Animals
• Brain Neoplasms (drug therapy)
• Cell Line, Tumor
• Female
• Glioblastoma (drug therapy)
• Humans
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Inbred BALB C
• Multiprotein Complexes (antagonists & inhibitors)
• Protein Kinase Inhibitors (therapeutic use)
• Sirolimus (therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Tacrolimus Binding Protein 1A (physiology)