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

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Pladevall Morera, David
María Castejón-Griñán
Paula Aguilera
Karina Gaardahl
Ingham, Andreas
Jacqueline A. Brosnan-Cashman
Alan K. Meeker
Lopez-Contreras, Andres

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.

Originalsprog	Engelsk
Artikelnummer	1790
Tidsskrift	Cancers
Vol/bind	14
Udgave nummer	7
ISSN	2072-6694
DOI	https://doi.org/10.3390/cancers14071790
Status	Udgivet - 2022

Bibliografisk note

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 Kr?ftforskningsfond. Mar?a Castej?n-Gri??n holds an Incorporaci?n fellowship from the Junta de Andaluc?a. Paula Aguilera was supported with a Juan de la Cierva formaci?n fellowship from the MICINN and an Incorpo-raci?n fellowship from the Junta de Andaluc?a. Toyota Fonden and L?ge 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.

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