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.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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


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