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A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

QiWen Fan1, Ozlem Aksoy1, Robyn A Wong1

  • 1Department of Neurology, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.

Cancer Cell
|March 16, 2017
PubMed

Insights

New mTOR kinase inhibitors (TORKi) like RapaLink-1 show improved efficacy in blocking mechanistic target of rapamycin (mTOR) in glioma, unlike older drugs. This study highlights mTOR as a key target for brain tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Signaling pathways involving PI3K/AKT/mTOR are frequently dysregulated in high-grade glial brain tumors.
  • Existing PI3K or AKT inhibitors have limited effects on downstream mTOR activity in gliomas.
  • Current allosteric mTOR inhibitors, like rapamycin, provide incomplete blockade of mTORC1 compared to mTOR kinase inhibitors (TORKi).

Purpose of the Study:

  • To compare the efficacy and durability of a novel TORKi, RapaLink-1, against earlier-generation mTOR inhibitors in glioma models.
  • To investigate the mechanism underlying RapaLink-1's enhanced activity, including its interaction with FKBP12.
  • To re-evaluate mechanistic target of rapamycin (mTOR) as a therapeutic target in glioma treatment.

Main Methods:

  • Comparative analysis of RapaLink-1, rapamycin, and other TORKi in preclinical glioma models.
  • Assessment of mTORC1 inhibition durability and potency.
  • Investigation of RapaLink-1 binding to FKBP12 and its impact on drug accumulation.

Main Results:

  • TORKi, including RapaLink-1, demonstrated superior inhibition of mTOR compared to rapamycin.
  • RapaLink-1 exhibited better efficacy and potency, particularly against cancer-derived activating mTOR mutants.
  • RapaLink-1's association with FKBP12 facilitated its accumulation and prolonged inhibition of mTORC1.
  • Earlier-generation TORKi showed poor durability of target inhibition.

Conclusions:

  • Mechanistic target of rapamycin (mTOR) remains a critical therapeutic target in high-grade glioma.
  • The limited efficacy of previous mTOR inhibitors is attributed to incomplete and non-durable inhibition of mTORC1.
  • RapaLink-1 represents a promising TORKi with enhanced durability and potency for glioma treatment.
Keywords:
FKBP12, FK506 binding protein 12FRB, FK506 rapamycin bindingGBM, glioblastomaPI3K, phosphatidylinositol 3' kinaseTORKi, mTOR kinase inhibitormTOR mechanistic target of rapamycinmTORC1, mTOR complex 1mTORC2, mTOR complex 2

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