Abexinostat attenuates temozolomide-resistant glioma stem cells

BACKGROUND: Glioblastoma (GBM) is the most common adult primary brain malignancy. Recent studies demonstrate that temozolomide (TMZ) facilitates the persistence of quiescent glioma stem cells (GSCs), which are responsible for GBM recurrence. An ideal therapy should eradicate both proliferating cells and GSCs. Abexinostat (Abx), a histone deacetylase inhibitor, was identified through connectivity mapping to target the specific GBM signature. Here, we demonstrate the anti-proliferative effect of Abx on both differentiated cells and GSCs. METHODS: Using patient-derived tumor cultures (PDCs) to test Abx in vitro, ATAC-seq identified chromatin accessibility. Single-spheroid and alkaline phosphatase staining assays were used to test stem cell self-renewal. Aldehyde dehydrogenase activity distinguished mesenchymal GSCs. The efficacy of Abx with TMZ was evaluated in GSC-expressing CK9751 PDC and mesenchymal patient-derived xenografts (PDXs). RESULTS: In PDCs (CK9495 and CK9751), Abx decreased the DNA repair machinery (RAD51, CHK1, Ku70, and MGMT) and induced apoptosis. Focused ATAC-seq analysis for promoters of DNA repair (RAD51, Ku70, CHK1, and BRCA1) and stemness (CD44, KLF4, c-Myc, and BMI1) revealed Abx decreased chromatin accessibility. Abx decreased stem cell self-renewal and reduced the mesenchymal stem cell signature (CD44, ALDH1A3 expression, and ALDH1 activity) in vitro GBM models. Abx reduced tumor growth and stemness markers in CK9751 PDC and mesenchymal PDXs. CONCLUSION: Abx reduced both DNA repair machinery and GSC markers by decreasing chromatin accessibility. Abx reduced tumor growth and mesenchymal GSCs in vitro and in vivo in GBM PDC and PDX models, supporting Abx's potential to prevent GSC-mediated therapy resistance and improve patient survival.