TY - JOUR
T1 - ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors
AU - Pladevall-Morera, David
AU - Castejón-Griñán, María
AU - Aguilera, Paula
AU - Gaardahl, Karina
AU - Ingham, Andreas
AU - Brosnan-Cashman, Jacqueline A.
AU - Meeker, Alan K.
AU - Lopez-Contreras, Andres J.
N1 - Funding Information:
This work was supported by grants from Danish National Research Foundation (DNRF115), Danish Cancer Society (KBVU-2017_R167-A11063), European Research Council (ERC-2015-STG-679068), Nordea-fonden (02-2017-1749) and the Spanish Ministry of Science and Innova-tion (PID2020-119329RB-I00). David Pladevall-Morera was supported with a PhD scholarship from the Lundbeck Foundation (R218-2016-415) and funding from Dansk Kræftforskningsfond. María Castejón-Griñán holds an Incorporación fellowship from the Junta de Andalucía. Paula Aguilera was supported with a Juan de la Cierva formación fellowship from the MICINN and an Incorpo-ración fellowship from the Junta de Andalucía. Toyota Fonden and Læge Sofus Carl Emil Friis og hustru Olga Doris Fonden funded the acquisition of the high-content microscope used in this study.
Funding Information:
Funding: This work was supported by grants from Danish National Research Foundation (DNRF115), Danish Cancer Society (KBVU-2017_R167-A11063), European Research Council (ERC-2015-STG-679068), Nordea-fonden (02-2017-1749) and the Spanish Ministry of Science and Innovation (PID2020-119329RB-I00). David Pladevall-Morera was supported with a PhD scholarship from the Lundbeck Foundation (R218-2016-415) and funding from Dansk Kræftforskningsfond. María Castejón-Griñán holds an Incorporación fellowship from the Junta de Andalucía. Paula Aguilera was supported with a Juan de la Cierva formación fellowship from the MICINN and an Incorpo-ración fellowship from the Junta de Andalucía. Toyota Fonden and Læge Sofus Carl Emil Friis og hustru Olga Doris Fonden funded the acquisition of the high-content microscope used in this study.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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 stand-ard 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 mu-tations. Thus, we recommend incorporating the ATRX status into the analyses of clinical trials with RTKi and PDGFRi.
AB - 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 stand-ard 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 mu-tations. Thus, we recommend incorporating the ATRX status into the analyses of clinical trials with RTKi and PDGFRi.
KW - ATRX
KW - PDGFRi
KW - RTKi
KW - drug screen
KW - glioblastoma
KW - glioma
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U2 - 10.3390/cancers14071790
DO - 10.3390/cancers14071790
M3 - Article
C2 - 35406561
AN - SCOPUS:85127448281
SN - 2072-6694
VL - 14
JO - Cancers
JF - Cancers
IS - 7
M1 - 1790
ER -