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Ciblage de la voie PI3K/mTOR dans les léiomyosarcomes : sensibilité et mécanismes de résistance

Abstract : Leiomyosarcomas (LMS) are tumors of mesenchymal origin characterized by a smooth cell differentiation. The PI3K/mTOR pathway has been shown to play a crucial role in the tumorigenesis of LMS. Several agents targeting this pathway are under clinical development for the treatment of solid tumors and hematological malignancies. We report here the first study evaluating its potential therapeutic benefit for patients with LMS. We have demonstrated that dual inhibition of PI3K and mTOR is associated with more effective antitumor activity than agents targeting PI3K or mTOR only. We have also shown that PI3K and mTOR inhibition is associated with a paradoxal activation of the MAPK pathway and that combined treatment with MEK inhibitor resulted in synergistic antitumor activity in vitro and in vivo. Moreover, we developed in vitro and in vivo resistant model to dual PI3K/mTOR inhibitor. Interestingly, we have found that a cancer stem cell-like subpopulation may be involved in treatment resistance. We have shown that pharmacological inhibition of EZH2, a crucial protein of the Polycomb complex, is able to reverse dual PI3K/mTOR inhibitor resistance in vitro and in vivo. These results provide new therapeutic strategies for patients with LMS.
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Submitted on : Tuesday, October 2, 2018 - 1:05:43 AM
Last modification on : Thursday, September 3, 2020 - 4:52:30 AM
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  • HAL Id : tel-01885499, version 1



Benjamin Fourneaux. Ciblage de la voie PI3K/mTOR dans les léiomyosarcomes : sensibilité et mécanismes de résistance. Médecine humaine et pathologie. Université de Bordeaux, 2017. Français. ⟨NNT : 2017BORD0742⟩. ⟨tel-01885499⟩



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