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A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.
Fan, QiWen; Aksoy, Ozlem; Wong, Robyn A; Ilkhanizadeh, Shirin; Novotny, Chris J; Gustafson, William C; Truong, Albert Yi-Que; Cayanan, Geraldine; Simonds, Erin F; Haas-Kogan, Daphne; Phillips, Joanna J; Nicolaides, Theodore; Okaniwa, Masanori; Shokat, Kevan M; Weiss, William A.
Affiliation
  • Fan Q; Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
  • Aksoy O; Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
  • Wong RA; Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
  • Ilkhanizadeh S; Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
  • Novotny CJ; Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  • Gustafson WC; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA.
  • Truong AY; Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
  • Cayanan G; Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
  • Simonds EF; Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
  • Haas-Kogan D; Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
  • Phillips JJ; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
  • Nicolaides T; Department of Pediatrics, University of California, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.
  • Okaniwa M; Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  • Shokat KM; Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  • Weiss WA; 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 Californ
Cancer Cell ; 31(3): 424-435, 2017 03 13.
Article in En | MEDLINE | ID: mdl-28292440
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Glioblastoma / Multiprotein Complexes / Protein Kinase Inhibitors / TOR Serine-Threonine Kinases Limits: Animals / Female / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2017 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Glioblastoma / Multiprotein Complexes / Protein Kinase Inhibitors / TOR Serine-Threonine Kinases Limits: Animals / Female / Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2017 Document type: Article Affiliation country: United States