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ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors

Department of Cellular and Molecular Medicine, DNRF Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla, Universidad Pablo de Olavide, 41013 Seville, Spain
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Ana María Zubiaga and Jone Mitxelena
Cancers 2022, 14(7), 1790;
Received: 15 February 2022 / Revised: 21 March 2022 / Accepted: 28 March 2022 / Published: 31 March 2022
(This article belongs to the Special Issue Genomic Instability in Tumor Evolution and Therapy Response)
High-grade glioma has a poor prognosis and new effective strategies to treat this aggressive form of cancer are highly needed. We have conducted a drug screen searching for compounds toxic to ATRX-deficient cells, a frequent scenario in cancer, and particularly in high-grade gliomas. We have identified that ATRX-deficient glioma cells are sensitive to several multi-targeted receptor tyrosine kinase and specific platelet-derived growth factor receptor inhibitors, some of which are currently under study in clinical trials. In view of our results, we believe that taking into consideration the presence/absence of ATRX mutations could provide valuable information to interpret the results of those clinical trials.
High-grade glioma, including anaplastic astrocytoma and glioblastoma (GBM) patients, have a poor prognosis due to the lack of effective treatments. Therefore, the development of new therapeutic strategies to treat these gliomas is urgently required. Given that high-grade gliomas frequently harbor mutations in the SNF2 family chromatin remodeler ATRX, we performed a screen to identify FDA-approved drugs that are toxic to ATRX-deficient cells. Our findings reveal that multi-targeted receptor tyrosine kinase (RTK) and platelet-derived growth factor receptor (PDGFR) inhibitors cause higher cellular toxicity in high-grade glioma ATRX-deficient cells. Furthermore, we demonstrate that a combinatorial treatment of RTKi with temozolomide (TMZ)–the current standard of care treatment for GBM patients–causes pronounced toxicity in ATRX-deficient high-grade glioma cells. Our findings suggest that combinatorial treatments with TMZ and RTKi may increase the therapeutic window of opportunity in patients who suffer high-grade gliomas with ATRX mutations. Thus, we recommend incorporating the ATRX status into the analyses of clinical trials with RTKi and PDGFRi. View Full-Text
Keywords: glioblastoma; glioma; ATRX; RTKi; PDGFRi; drug screen glioblastoma; glioma; ATRX; RTKi; PDGFRi; drug screen
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MDPI and ACS Style

Pladevall-Morera, D.; Castejón-Griñán, M.; Aguilera, P.; Gaardahl, K.; Ingham, A.; Brosnan-Cashman, J.A.; Meeker, A.K.; Lopez-Contreras, A.J. ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors. Cancers 2022, 14, 1790.

AMA Style

Pladevall-Morera D, Castejón-Griñán M, Aguilera P, Gaardahl K, Ingham A, Brosnan-Cashman JA, Meeker AK, Lopez-Contreras AJ. ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors. Cancers. 2022; 14(7):1790.

Chicago/Turabian Style

Pladevall-Morera, David, María Castejón-Griñán, Paula Aguilera, Karina Gaardahl, Andreas Ingham, Jacqueline A. Brosnan-Cashman, Alan K. Meeker, and Andres J. Lopez-Contreras. 2022. "ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors" Cancers 14, no. 7: 1790.

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