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Fonctionnalité de la signalisation en aval des récepteurs HER : implication dans la réponse cellulaire et tumorale aux thérapies ciblées

Abstract : Targeted therapies, monoclonal antibodies and tyrosine kinase inhibitors, directed against the Human Epidermal Growth Factor Receptors (HER) family, represent a major advance in oncology. Their efficacy depends on their ability to inhibit oncogenic signalling, including the RAS/RAF/MAPK and PI3K/AKT signalling pathways. Regardless of the expression of the molecular target, the efficacy of targeted therapies is independent on the genetic abnormalities of the tissue which are able to disrupt tumour cell signalling, and the research of these abnormalities is now included in the prescription criteria. The aim of this work was to evaluate the usefulness of assessing HER downstream signalling functionality using multiplex analysis of the phosphorylated forms of key intracellular kinase signalling. Proof of concept was first introduced with genetically modified cell lines models, showing the consequences of tumour genetic abnormalities on RAS/RAF/MAPK and PI3K/AKT signalling pathways and on response to cetuximab. In the second part of this work, after validation of the techniques used in clinical situation, we demonstrated the relevance of system biology approach, combining molecular biology and functional analysis with principal component analysis. Our results obtained in a retrospective clinical study in metastatic colorectal cancer, suggests that the use of data from the evaluation of HER downstream signalling pathways functionality could eventually find applications as predictive markers of clinical response to anti-HER targeted therapies
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Anne-Sophie Chrétien. Fonctionnalité de la signalisation en aval des récepteurs HER : implication dans la réponse cellulaire et tumorale aux thérapies ciblées. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2011. Français. ⟨NNT : 2011NAN10050⟩. ⟨tel-01746205⟩

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