Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma

Aldaz, Paula and Auzmendi-Iriarte, Jaione and Durántez, Maika and Lasheras-Otero, Irene and Carrasco-Garcia, Estefania and Zelaya, M. Victoria and Bragado, Laura and Olías-Arjona, Ana and Egaña, Larraitz and Samprón, Nicolás and Morilla, Idoia and Redondo-Muñoz, Marta and Rico, Mikel and Squatrito, Massimo and Maria-Alonso, Marta and Fernández-Irigoyen, Joaquín and Santamaria, Enrique and Larráyoz, Iñaki M. and Wellbrock, Claudia and Matheu, Ander and Arozarena, Imanol (2021) Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma. Cancers, 13 (2). p. 361. ISSN 2072-6694

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Abstract

(1) Background: Despite the indisputable effectiveness of dexamethasone (DEXA) to reduce inflammation in glioblastoma (GBM) patients, its influence on tumour progression and radiotherapy response remains controversial. (2) Methods: We analysed patient data and used expression and cell biological analyses to assess effects of DEXA on GBM cells. We tested the efficacy of tyrosine kinase inhibitors in vitro and in vivo. (3) Results: We confirm in our patient cohort that administration of DEXA correlates with worse overall survival and shorter time to relapse. In GBM cells and glioma stem-like cells (GSCs) DEXA down-regulates genes controlling G2/M and mitotic-spindle checkpoints, and it enables cells to override the spindle assembly checkpoint (SAC). Concurrently, DEXA up-regulates Platelet Derived Growth Factor Receptor (PDGFR) signalling, which stimulates expression of anti-apoptotic regulators BCL2L1 and MCL1, required for survival during extended mitosis. Importantly, the protective potential of DEXA is dependent on intact tyrosine kinase signalling and ponatinib, sunitinib and dasatinib, all effectively overcome the radio-protective and pro-proliferative activity of DEXA. Moreover, we discovered that DEXA-induced signalling creates a therapeutic vulnerability for sunitinib in GSCs and GBM cells in vitro and in vivo. (4) Conclusions: Our results reveal a novel DEXA-induced mechanism in GBM cells and provide a rationale for revisiting the use of tyrosine kinase inhibitors for the treatment of GBM.

Item Type: Article
Subjects: European Repository > Medical Science
Depositing User: Managing Editor
Date Deposited: 15 Feb 2023 04:35
Last Modified: 15 Apr 2024 10:21
URI: http://go7publish.com/id/eprint/476

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