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

SIMPLE SUMMARY: 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. 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.