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Sensibilisation aux drogues chimiothérapeutiques des tumeurs P53 négatives par activation de la phosphatase Wip1

Abstract : P53 is mutated in more than half of human cancers and when inactivated is often associated with a resistance to anti-cancer therapy. Our team has hown that in the case of p53-negative tumors, overexpression of Wip1 phosphatase sensitizes tumor cells to chemotherapy, while protecting normal tissues from the side effects of the treatment. To improve this strategy, two main objectives were studied. Firstly, to find a protein which can interact with Wip1 pathway and potentiate its action in this therapeutic strategy. Secondly, to find a molecule which can activate Wip1. We realized a siRNA screening of the whole human kinome to identify several kinases, whose inhibition could potentiate anti-tumoral action of Wip1. We have shown that Wee1 and Hipk2, which both have available inhibitors, have an action on Wip1 pathway. Inhibiting Wee1 with a low dose of MK-1775, a specific inhibitor of this kinase, allowed us to decrease effective cisplatin concentration, inducing a caspase-3-dependent apoptosis. Moreover, the combination of MK-1775 with Wip1 overexpression does not impair the protective effect that this phosphatase provides towards normal tissues. We then showed that the Vorinostat, an HDAC inhibitor, induces an increase in Wip1 transcription in breast cancer cells with inactive p53. This work uncovered a way to potentiate the Wip1-based therapeutic strategy of p53-negative tumors.
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Submitted on : Tuesday, April 9, 2019 - 4:50:07 PM
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Victor Clausse. Sensibilisation aux drogues chimiothérapeutiques des tumeurs P53 négatives par activation de la phosphatase Wip1. Sciences agricoles. Université Bourgogne Franche-Comté, 2017. Français. ⟨NNT : 2017UBFCI002⟩. ⟨tel-02094528⟩

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