Gene Expression-Based Drug Repurposing Predicted GSK-2126458 and KU-0060648 as Candidate Small Molecules for...

Glioblastoma (GBM) has the poorest prognosis among primary brain tumors. Owing to the marked heterogeneity among GBM patients, effective treatment remains challenging. Therefore, there is a critical need to identify molecular signatures that play key roles in GBM pathogenesis, as well as to develop novel therapeutic targets and drug candidates. In this study, we performed a systems biology pipeline to identify the potential drug candidates for treating GBM patients and experimental studies to understand the effect of identified repurposed drugs on T98G cells, human glioblastoma cell line. As a result of systems biology and and text mining analyses, three drugs or small molecules were identified as repurposing candidates for GBM. It was identified that two FDA-approved drugs, GSK-2126458/Omipalisib (TF-IDF value = 0.019) and KU 0060648/trihydrochloride (TF-IDF value = 0) and vorinostat (TF-IDF value = 0.29), which is frequently studied in GBM may be promising candidates for GBM. T98G, human glioblastoma cell line, was used in cell culture experiments for validation studies. The IC50 values were determined as 0.40 µM for GSK-2126458, 3.5 µM for KU-0060648, and 30 µM for Vorinostat drug molecules. Proposed drug molecules showed lower IC50 concentrations addressing lower dose usages for treatment options when compared to the vorinostat. The increased occurrence of vacuolized cells together with the detection of apoptotic markers may indicate a possible involvement of KU-0060648 in autophagy-associated apoptotic processes; however, additional studies are needed to clarify the underlying mechanisms. GSK-2126458 drug molecule showed the lowest IC50 value with 0.40 µM and triggered necrosis with 26.6% PI positive cell labeling. Further in vitro and in vivo validation of both small molecules may provide new treatment options for GBM.