Activated MEK cooperates with Ink4a/Arf loss or Akt activation to induce gliomas in vivo

J. P. Robinson, M. W. Vanbrocklin, K. J. Lastwika, A. J. McKinney, S. Brandner, S. L. Holmen

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The RAS/RAF mitogen-activated protein kinase pathway (MAPK) is highly active in many tumor types including the majority of high-grade gliomas and expression of activated RAS or RAF in neural progenitor cells combined with either AKT activation or Ink4a/Arf loss leads to the development of high-grade gliomas in vivo. This strongly suggests that this pathway is necessary for glioma formation and maintenance. To further define the role of this pathway in the development of high-grade gliomas, we used the established RCAS/TVA glioma mouse model to test the ability of activated MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK), a RAF effector, to induce tumors in vivo in the context of activated AKT or Ink4a/Arf loss. Although expression of activated MEK alone in neural progenitor cells is not sufficient for tumorigenesis, the combination of activated MEK and AKT or MEK with Ink4a/Arf loss is transforming. The data reveal that activation of the classical RAS/MAPK pathway, which is mediated through MEK, leads to the development of high-grade gliomas in vivo and suggest that MEK may be a relevant target for glioma therapy. To test this, we treated both mouse and human glioma cells with the MEK inhibitor PD0325901. Although this treatment induced apoptosis in a significant percentage of the cells, the effect was enhanced by combined treatment with the phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235. Our results demonstrate that combined inhibition of MEK and PI3K/mTOR is a rational strategy for the treatment of high-grade gliomas and may be an effective adjuvant therapy for this disease.

Original languageEnglish (US)
Pages (from-to)1341-1350
Number of pages10
JournalOncogene
Volume30
Issue number11
DOIs
StatePublished - Mar 17 2011
Externally publishedYes

Bibliographical note

Funding Information:
We thank Han-Mo Koo, Eric Holland and Ronald DePinho for reagents and advice. We thank James Symanowski for assistance with statistical analysis of the data. We also thank Novartis Pharmaceuticals for providing the NVP-BEZ235. This work was supported by the Nevada Cancer Institute, the National Brain Tumor Foundation and RSG-06-198-01-TBE from the American Cancer Society.

Keywords

  • AKT
  • Ink4a/Arf
  • MEK
  • glioma
  • mouse model
  • targeted therapy

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