mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma

Neuro Oncol. 2014 Apr;16(4):493-504. doi: 10.1093/neuonc/not242. Epub 2014 Jan 10.


Background: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach.

Methods: We studied in vitro cell models, cohorts of mice allografted with Nf2(-/-) Schwann cells, and a genetically modified mouse model of NF2 schwannoma in order to evaluate the efficacy of the proposed targeted therapy for NF2.

Results: We found that treatment with the mTORC1 inhibitor rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis without significant toxicity. Consistent with these results, in an NF2 patient with growing vestibular schwannomas, the rapalog sirolimus induced tumor growth arrest.

Conclusions: Taken together, these results constitute definitive evidence that justifies proceeding with clinical trials using mTORC1-targeted agents in selected patients with NF2 and in patients with NF2-related sporadic tumors.

Keywords: neurofibromatosis type 2; rapamycin; schwannoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cell Size / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoenzyme Techniques
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / metabolism
  • Neurilemmoma / metabolism
  • Neurilemmoma / pathology
  • Neurilemmoma / prevention & control*
  • Neurofibromatosis 2 / metabolism
  • Neurofibromatosis 2 / pathology
  • Neurofibromatosis 2 / prevention & control*
  • Neurofibromin 2 / physiology*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured


  • Multiprotein Complexes
  • Neurofibromin 2
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus