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

Oncogene volume 30, pages 1341–1350 (2011)Cite this article

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Drug Development Department, Nevada Cancer Institute, Las Vegas, NV, USA

    J P Robinson, M W VanBrocklin, K J Lastwika, A J McKinney & S L Holmen

  2. Division of Neuropathology, UCL Institute of Neurology, London, UK

    S Brandner

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  1. J P Robinson
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  2. M W VanBrocklin
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Correspondence to S L Holmen.

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Robinson, J., VanBrocklin, M., Lastwika, K. et al. Activated MEK cooperates with Ink4a/Arf loss or Akt activation to induce gliomas in vivo. Oncogene 30, 1341–1350 (2011). https://doi.org/10.1038/onc.2010.513

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