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PMID: 28292440 Published · ppublish English Journal Article

A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.

Cancer cell ·Vol. 31 ·No. 3 ·2017-00-13 ·Pages 424-435

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 WA

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
Chemicals
Multiprotein Complexes Protein Kinase Inhibitors Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases Tacrolimus Binding Protein 1A Sirolimus
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Fan QiWen
Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Aksoy Ozlem
Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Wong Robyn A
Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Ilkhanizadeh Shirin
Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Novotny Chris J
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Gustafson William C
Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA.
Truong Albert Yi-Que
Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
Cayanan Geraldine
Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Simonds Erin F
Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
Haas-Kogan Daphne
Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
Phillips Joanna J
Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
Nicolaides Theodore
Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
Okaniwa Masanori
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Shokat Kevan M
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Weiss William A
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: [email protected].
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccell.2017.01.014
Email
[email protected]
Published
2017-00-13
Pages
424-435
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC5386178
Subset
IM
Grants
NCI NIH HHS · U54 CA163155 · United States
NCI NIH HHS · U01 CA176287 · United States
NINDS NIH HHS · R01 NS091620 · United States
NCI NIH HHS · P01 CA118816 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P30 CA082103 · United States
NCI NIH HHS · R01 CA148699 · United States
NINDS NIH HHS · R01 NS089868 · United States
NIGMS NIH HHS · T32 GM064337 · United States
NIAAA NIH HHS · P50 AA017072 · United States
Corrections
CommentIn
PMID: 28377407
External Links
PubMed source DOI: 10.1016/j.ccell.2017.01.014 PMC Full Text View journal details
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