title: 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.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: QiWen
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Aksoy
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Wong
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Shirin
authors.initials: S
authors.lastname: Ilkhanizadeh
authors.affiliation: Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Novotny
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Gustafson
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
authors.forename: Albert Yi-Que
authors.initials: AY
authors.lastname: Truong
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cayanan
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Erin F
authors.initials: EF
authors.lastname: Simonds
authors.affiliation: Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Daphne
authors.initials: D
authors.lastname: Haas-Kogan
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
authors.affiliation: Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Okaniwa
authors.affiliation: Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: 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.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D022061:Tacrolimus Binding Protein 1A / Q000502:physiology
chemical_list: D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus
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