ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors
David Pladevall-Morera1, María Castejón-Griñán1,2, Paula Aguilera1,2
1Department of Cellular and Molecular Medicine, DNRF Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
Abstract:
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.
Insights
Targeting ATRX-deficient high-grade gliomas with receptor tyrosine kinase inhibitors (RTKi) shows promise. Combining RTKi with temozolomide (TMZ) enhances toxicity in these aggressive brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High-grade gliomas, including glioblastoma (GBM), have a poor prognosis due to limited treatment options.
- Mutations in the ATRX gene are common in high-grade gliomas, suggesting it as a potential therapeutic target.
Purpose of the Study:
- To identify FDA-approved drugs effective against ATRX-deficient high-grade glioma cells.
- To evaluate the efficacy of combining receptor tyrosine kinase inhibitors (RTKi) with temozolomide (TMZ) in ATRX-mutated gliomas.
Main Methods:
- Screening of FDA-approved drugs for toxicity in ATRX-deficient glioma cells.
- Assessment of cellular toxicity of multi-targeted RTK and PDGFR inhibitors.
- Evaluation of combinatorial treatment effects of RTKi and TMZ on ATRX-deficient glioma cells.
Main Results:
- Multi-targeted RTK and PDGFR inhibitors demonstrated significant toxicity towards ATRX-deficient high-grade glioma cells.
- Combinatorial treatment with RTKi and TMZ resulted in pronounced toxicity in ATRX-deficient high-grade glioma cells.
- The study identified specific drug classes effective against a common genetic alteration in gliomas.
Conclusions:
- Receptor tyrosine kinase inhibitors (RTKi) show potential as a therapeutic strategy for ATRX-mutated high-grade gliomas.
- Combining RTKi with temozolomide (TMZ) may improve treatment outcomes for GBM patients with ATRX mutations.
- Incorporating ATRX mutation status in clinical trial analysis for RTKi and PDGFR inhibitors is recommended.
