Rôle du récepteur des xénobiotiques PXR (Pregnane X Receptor) et de ses gènes cibles sur la sensibilité des lignées de cancer de prostate aux inhibiteurs de kinases

Abstract : More and more kinase inhibitors (KIs) are tested in prostate cancer that represents a major health issue in men with its incidence and mortality rates. Clinical trials to evaluate KIs efficacy in prostate cancer gave disapointing results depsite the presence of KIs pharmacological targets in prostate tumors (VEGF, EGFR, CMET..), suggesting that inefficiency of these drugs would be at least in part linked to the inhibitor itself or its pharmacodynamics/pharmacokinetics parameters. Indeed KIs are metabolized and transported via phase I and II enzymes that are mainly controlled by the xenoreceptor PXR (Pregnane X Receptor, gène NR1I2). It is mainly expressed in liver and gastro-intestinal tract but also in epithelial tumors. PXR is also involved in the resistance to chemotherapies by increasing the catabolism and the efflux of these anticancer agents. To date only one study evaluated PXR expression in prostate cancer without evaluating its impact on treatment efficacy. In collaboration with Pr G. Fromont we analyzed a cohort of 449 prostate tumors and observed that PXR was more frequently detected in castration resistant or metastatic tumors as compared to clinically localized forms in which PXR expression was significantly correlated with TNM and ISUP Score. These results confirmed the interest to study the potential role of PXR and its target genes in the sensitivity to kinase inhibitors in prostate cancer models.We measured the expression of PXR and its target genes in prostate cancer cell lines 22RV1, LnCap, PC3 and DU145. The results showed that enzymes and transporters involved in KI detoxification was significantly expressed in these cells whereasPXR was poorly expressed due to hypermethylation of NR1I2 in our cells. This lead us to develop specific prostate cancer cell models stably overexpressing PXR in which transcriptional activity of PXR can be induced by its known agonist SR12813 further indicating that prostate cancer cells are metabolically competent. Using these models we showed that PXR overexpression modulates the sensitivity of 22RV1 cells to erlotinib, dasatinib, dabrafenib and afatinib, demonstrating that PXR plays a functional role in the sensitivity to KIs. We also demonstrated that several KIs were PXR agonists, including dabrafenib that displayed enhanced agonistic properties as compared to SR12813, a result that was never published before. This original finding led us to engage the cristalization of PXR/dabrafenib complex and to test whether induction of PXR could lead to an alteration of metabolism and transport of other drugs that are co-administered. In this line we have observed that in 22RV1 cells the additive effect of the combination of dabrafenib with trametinib that is already approved in the treatment of melanomas, became antagonistic when PXR was overexpressed in these cells. This result is supporting our hypothesis though we still need to demonstrate that this effect is linked to a change in drugs metabolism, which is currently under investigation by the measurement of the known metabolites of these KIs.Altogether, our data could serve as rational basis for the choice of kinase inhibitors or their potential combinations that could be tested in further clinical trials alone or in association with hormone therapies or with chemotherapies that are currently prescribed in the treatment of advanced prostate cancers, in order to potentiate tumor response.
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Matthieu Gassiot. Rôle du récepteur des xénobiotiques PXR (Pregnane X Receptor) et de ses gènes cibles sur la sensibilité des lignées de cancer de prostate aux inhibiteurs de kinases. Médecine humaine et pathologie. Université Montpellier, 2017. Français. ⟨NNT : 2017MONTT133⟩. ⟨tel-02356082⟩

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