Artículo
ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors
Autor/es | Pladevall Morera, David
Castejón Griñán, María Aguilera, Paula Gaardahl, Karina Ingham, Andreas Brosnan Cashman, Jacqueline A. Meeker, Alan K. López Contreras, Andrés J. |
Fecha de publicación | 2022 |
Fecha de depósito | 2022-04-20 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España European Research Council (ERC) Danish Cancer Society Danish National Research Foundation |
Identificador del proyecto | (DNRF115)
(KBVU-2017_R167-A11063) (PID2020- 119329RB-I00) (ERC-2015-STG679068) |
Cita | Pladevall Morera, D., Castejón Griñán, M., Aguilera, P., Gaardahl, K., Ingham, ., Brosnan Cashman, J.A.,...,López Contreras, A.J. (2022). ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors. Cancers, 14 (7), 1790. |
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