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Article

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

1
Department of Cellular and Molecular Medicine, DNRF Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark
2
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
3
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; https://doi.org/10.3390/cancers14071790
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. https://doi.org/10.3390/cancers14071790

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. https://doi.org/10.3390/cancers14071790

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. https://doi.org/10.3390/cancers14071790

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