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P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab

Cancer Gene Therapy volume 16, pages 498–507 (2009)Cite this article

Abstract

Cetuximab (Erbitux) is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody whose activity is related to the inhibition of EGFR downstream signaling pathways. P53 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been reported to control the functionality of PI3K/AKT signaling. In this study we evaluated whether reintroducing P53 using non-viral gene transfer enhances PTEN-mediated inhibition of PI3K/AKT signaling by cetuximab in PC3 prostate adenocarcinoma cell line bearing p53 and pten mutations. Signaling phosphoproteins expression was analyzed using Bio-Plex phosphoprotein array and western blot. Apoptosis induction was evaluated from BAX expression, caspase-3 activation and DNA fragmentation analyses. The results presented show that p53 and pten gene transfer additionally mediated cell growth inhibition and apoptosis induction by restoral of signaling functionality, which enabled the control of PI3K/AKT and MAPKinase signaling pathways by cetuximab in PC3 cells. These results highlight the interest of the analysis of signaling phosphoproteins expression as molecular predictive markers for response to cetuximab and show that p53 and pten mutations could be key determinants of cell response to cetuximab through the functional impact of these mutations on cell signaling.

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Acknowledgements

This study was supported by grants from the French Ligue Nationale Contre le Cancer and Alexis Vautrin Cancer Center private research funds.

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Authors and Affiliations

  1. Centre Alexis Vautrin, Unité de Biologie des Tumeurs, EA “Predicther” Nancy Université, Vandœuvre-lès-Nancy cedex, France

    S Bouali, A-S Chrétien, C Ramacci, M Rouyer & J-L Merlin

  2. Centre Alexis Vautrin, CRAN UMR 7039 CNRS-UHP-INPL, Vandœuvre-lès-Nancy cedex, France

    S Marchal

  3. INSERM U601, CHU de Nantes, Institut de Biologie, Nantes, France

    T Galenne & P Juin

  4. Laboratoire de Biologie Cellulaire, Faculté des Sciences, EA “Predicther” Nancy Université, Vandœuvre-lès-Nancy, France

    P Becuwe

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Correspondence to J-L Merlin.

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Bouali, S., Chrétien, AS., Ramacci, C. et al. P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab. Cancer Gene Ther 16, 498–507 (2009). https://doi.org/10.1038/cgt.2008.100

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  • DOI: https://doi.org/10.1038/cgt.2008.100

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