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Transfert des gènes p53 et pten par vectorisation non virale : effet pro-apoptotique et potentialisation de la réponse cellulaire au cétuximab

Abstract : P53 and PTEN abnormalities are early events in carcinogenesis and are associated with poor prognosis and resistance to cancer therapies including targeted therapy. Cetuxirnab (Erbitnx®) is a IgG chimeric monoclonal antibody, directed against the extracellular dornain of EGFR. !ts activity has been shown to be dependent on the functionality of PI3KJAKT and MAPK signaling pathways as weil as the apoptosis induction capacity of the cells . The present study was designed to evaluate the influence of pten and p53 gene transfer using polyethylenimine with or without photochemical internalisation on cell apoptosis induction and cell growth in cells bearing p53 and pten mutations and on the response to cetuximab. The results presented show that pten and p53 gene transfer using polyethertimine and PCI restored P53 and PTEN expression, cell growth inhibition and apoptosis induction. Associated with cetuximab treatrnent, pten and p53 reintroduction, restored the functionality of AKTIPI3K and MAPK signaling pathways and increased cell growth inhibition and apoptosis induction by cetuximab. The results achieved in the present study show that pten and p53 mutations could be predictive of cell response to cetuximab through the functional impact of these mutations on cell signaling. The data presented put forward the interest of the analysis of EGFR phosphoproteins downstream signalling to evaluate the functionality of the signaling pathways implicated in the cell response to cetuximab and could be used to propose the original targeted therapies.
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Sanae Bouali. Transfert des gènes p53 et pten par vectorisation non virale : effet pro-apoptotique et potentialisation de la réponse cellulaire au cétuximab. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2008. Français. ⟨NNT : 2008NAN10147⟩. ⟨tel-01777253⟩

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