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

Paula Aldaz,Irene Lasheras-Otero,Maika Durántez,Marta Maria-Alonso,Marta Redondo-Muñoz,Larraitz Egaña,Massimo Squatrito,Idoia Morilla,Ander Matheu,Claudia Wellbrock,Imanol Arozarena,Jaione Auzmendi-Iriarte,Nicolás Samprón,Ana Olías-Arjona,M Rico ,María Victoria Zelaya ,Iñaki M Larráyoz ,Enrique Santamaría ,L Bragado ,Joaquín Fernández‐Irigoyen ,Estefanía Carrasco‐García

doi:10.3390/cancers13020361

Abstract

Simple SummaryThe standard of care for patients with newly diagnosed glioblastoma (GBM) comprises surgery followed by radio- and chemotherapy. In addition, dexamethasone is used to manage the development of inflammation within the brain in general, and particularly during treatment. The effects of dexamethasone on patient survival however remain controversial because several clinical studies suggest that dexamethasone could potentially restrict effective radiotherapy. With the idea to improve GBM therapy, we set out to identify small molecule inhibitors that could improve the killing of GBM cells when applied together with radiotherapy. We have identified a novel dexamethasone-induced mechanism that can directly protect GBM cells from radiotherapy and thus may contribute to the adverse effects observed in the clinic. Strikingly, this mechanism also sensitises GBM cells to tyrosine kinase inhibitors, thus encouraging the revision of the use of these inhibitors for the treatment of GBM, potentially in an adjuvant setting.(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.

Highlights

Glioblastoma (GBM) remains among the cancers with poorest prognosis with a median overall survival of only 15 months after diagnosis [1]
DEXA administration correlated with significantly shorter overall survival after surgery, and this effect was seen in the cohort of patients who had received radiotherapy after surgery (Figure 1C,D)
We demonstrate that DEXA can propagate GBM cell growth even some time after radiation, suggesting that the ability of DEXA to override the spindle assembly checkpoint (SAC) promotes continued proliferation despite DNA damage

Summary

Introduction

Glioblastoma (GBM) remains among the cancers with poorest prognosis with a median overall survival of only 15 months after diagnosis [1]. Genome-wide analyses of large patient cohorts have revealed clinically relevant GBM subtypes such as classical, proneural or mesenchymal, which correlate with particular tumour microenvironments and have prognostic implications [3,4,5]. Radiotherapy is the standard of care for GBM after surgical resection, but the vast majority of patients relapse due to intrinsic or acquired resistance. Acquired resistance to radiotherapy is thought to rely on the deregulation of DNA repair mechanisms, cell cycle progression and survival pathways in GBM cells, and on signals from the stroma, including a hypoxic extracellular environment [6]. Sub-populations of undifferentiated glioblastoma stem-like cells (GSCs) that show increased resistance to radiotherapy are thought to cause tumour relapse [6]

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