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Identification de la protéine chaperonne FKBP7 comme une nouvelle cible thérapeutique dans le cancer de la prostate résistant à la chimiothérapie

Abstract : Prostate cancer is the second cancer diagnosed among men worldwide. Beside approval of new therapies in the last five years, chemotherapeutic agents, docetaxel and cabazitaxel taxanes remain key treatments for metastatic castration resistant prostate cancers. However, primary and acquired resistance to taxanes still emerged in about half of patients. There is therefore an urgent need to discover and understand the taxane resistance mechanisms in order to identify new therapeutic targets. Indeed, targeted therapies that exploit the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes. Molecular chaperones play a key role in the regulation of cellular homeostasis and the development of treatment resistance, and are promising therapeutic targets. Using high throughput siRNA functional screening based on a gene expression signature, we identified FKBP7, involved in acquired resistance to docetaxel and cabazitaxel. FKBP7 is a molecular chaperone that has not been studied in human so far. FKBP7 is overexpressed in prostate tumors and its expression is correlated with recurrence in patients who received docetaxel as neoadjuvant therapy. Moreover, FKBP7 is upregulated in taxane resistant prostate cancer cell lines and its expression sustains their growth in vitro and in a mice model of Docetaxel resistance. Using a high throughput proteomic approach, we identified the signaling pathway regulated by FKBP7 which is responsible for the survival of chemoresistant cells. Finally, we proposed a promising therapeutic strategy to overcome both docetaxel and cabazitaxel chemoresistance by targeting the downstream effector of FKBP7.
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https://tel.archives-ouvertes.fr/tel-01674190
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Submitted on : Tuesday, January 2, 2018 - 1:34:47 AM
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Marine Garrido. Identification de la protéine chaperonne FKBP7 comme une nouvelle cible thérapeutique dans le cancer de la prostate résistant à la chimiothérapie. Cancer. Université Paris Saclay (COmUE), 2016. Français. ⟨NNT : 2016SACLS181⟩. ⟨tel-01674190⟩

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