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INK4a/Arf is required for suppression of EGFR/ΔEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma

Oncogene volume 23, pages 6854–6863 (2004)Cite this article

An Erratum to this article was published on 03 February 2005

Abstract

Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant, ΔEGFR(2–7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16INK4a/p19Arf or p53, respectively, with or without ectopic expression of ΔEGFR(2–7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of ΔEGFR(2–7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/ΔEGFR(2–7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/ΔEGFR(2–7) in glioblastoma patients.

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Acknowledgements

We are indebted to HJ Su Huang for the vectors pBluescript.EGFR and pBluescript.ΔEGFR(2–7), and to O Bögler for the retroviral vectors 1726/Zeo.EGFR and 1726/Zeo.ΔEGFR(2–7). We thank L Donehower for the TP53-KO mice and to M Serrano for the INK4a/Arf-KO mice. We thank RC Janzer for tumor histology and T Roger for positive controls for ERK phosphorylation. We also thank A Merlo for helpful discussions and I Desbaillets for critical reading of the manuscript. This project was supported by grants of Swiss Cancer Research and OncoSuisse (to MEH and NdT)

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Authors and Affiliations

  1. Department of Neurosurgery, Laboratory of Tumor Biology and Genetics, University Hospital (CHUV), Lausanne, BH19-110, 1011, Switzerland

    Yan Lachat, Annie-Claire Diserens, Michimasa Nozaki, Hiroyuki Kobayashi, Marie-France Hamou, Sophie Godard, Nicolas de Tribolet & Monika E Hegi

  2. National Center of Competence (NCCR) Molecular Oncology, ISREC, Epalinges, 1066, Switzerland

    Monika E Hegi

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  1. Yan Lachat
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Correspondence to Monika E Hegi.

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Lachat, Y., Diserens, AC., Nozaki, M. et al. INK4a/Arf is required for suppression of EGFR/ΔEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma. Oncogene 23, 6854–6863 (2004). https://doi.org/10.1038/sj.onc.1207872

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