A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

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

doi:10.1016/j.ccell.2017.01.014

A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

Cancer Cell. 2017 Mar 13;31(3):424-435. doi: 10.1016/j.ccell.2017.01.014.

Authors

Affiliations

¹ Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
² Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
³ Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA.
⁴ Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
⁵ Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
⁷ Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA. Electronic address: waweiss@gmail.com.

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.

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.

MeSH terms

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

Substances

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

Abstract

MeSH terms

Substances

Grants and funding