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E2F1-dependent oncogenic addiction of melanoma cells to MDM2

Oncogene volume 31, pages 828–841 (2012)Cite this article

Abstract

One of the defining features of aggressive melanomas is their complexity. Hundreds of mutations and an ever increasing list of changes in the transcriptome and proteome distinguish normal from malignant melanocytic cells. Yet, despite this altered genetic background, a long-known attribute of melanomas is a relatively low rate of mutations in the p53 gene. However, it is unclear whether p53 is maintained in melanoma cells because it is required for their survival, or because it is functionally disabled. More pressing from a translational perspective, is to define whether there is a tumor cell-selective wiring of p53 that offers a window for therapeutic intervention. Here, we provide genetic and pharmacological evidence demonstrating that p53 represents a liability to melanoma cells, which they thwart by assuming an oncogenic dependency on the E3 ligase murine double minute-2 (MDM2). Specifically, we used a combination of RNA interference and two structurally independent small molecule inhibitors of the p53–MDM2 interaction to assess the relative requirement of both proteins for the viability of normal melanocytes and a broad panel of melanoma cell lines. We demonstrated in vitro and in vivo that MDM2 is selectively required to blunt latent pro-senescence signals in melanoma cells. Notably, the outcome of MDM2 inactivation depends not only on the mutational status of p53, but also on its ability to signal to the transcription factor E2F1. These data support MDM2 as a drug target in melanoma cells, and identify E2F1 as a biomarker to consider when stratifying putative candidates for clinical studies of p53–MDM2 inhibitors.

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Acknowledgements

We thank Joshua A Bauer, J Chadwick Brenner and Thomas E Carey for shRNA constructs against p53 and MDM2, Andrzej Dlugosz for support and Mikhail Nikiforov for helpful suggestions at early stages of this study. MSS was supported by R01CA107237 from the NIH, SAF2008-01950 from the Spanish Ministry of Science and Innovation, and a development grant from the Spanish Association Against Cancer (AECC). SW was funded by R01CA121279 and MV is the recipient of a Career Development Award from the Dermatology Foundation.

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Authors and Affiliations

  1. Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA

    M Verhaegen & M B Riblett

  2. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA

    M Verhaegen, M B Riblett & S Wang

  3. Melanoma Laboratory, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO) (Spanish National Cancer Research Centre), Madrid, Spain

    A Checinska & M S Soengas

  4. Department of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor, MI, USA

    S Wang

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  1. M Verhaegen
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  5. M S Soengas
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Correspondence to M S Soengas.

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Competing interests

The p53–MDM2-binding inhibitor MI-219 was licensed by the University of Michigan to Ascenta Therapeutics Inc. (Malvern, PA, USA), and has been subsequently sub-licensed to Sanofi-Aventis (Bridgewater, NJ, USA). Shaomeng Wang owns stocks and serves as a consultant in Ascenta Therapeutics. The University of Michigan also owns stocks in Ascenta Therapeutics and receives milestone and royalty payments from Ascenta and Sanofi-Aventis.

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Verhaegen, M., Checinska, A., Riblett, M. et al. E2F1-dependent oncogenic addiction of melanoma cells to MDM2. Oncogene 31, 828–841 (2012). https://doi.org/10.1038/onc.2011.277

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