Glioblastoma (GBM) is a highly invasive malignancy of the central nervous system characterized by poor therapeutic responsiveness. Temozolomide (TMZ) is a chemotherapeutic agent routinely used in the treatment of patients with GBM. TAS-115 is a multi-target receptor tyrosine kinase inhibitor that suppresses c-Met, VEGFR, and PDGFR signaling pathways. In the present study, the effects of TAS-115 on cell viability were, for the first time, evaluated in vitro in U87MG cells as well as in patient-derived TMZ-sensitive primary GBM cells.

: TMZ-sensitive U87MG and patient-derived primary GBM cells were utilized in this study. The experimental design specifically focused on TMZ responsiveness, and all assays were performed in parallel in both cell groups (U87MG and primary cells). Initially, the half-maximal inhibitory concentration (IC₅₀) values of TMZ and TAS-115 were determined using the MTT assay. Subsequently, proliferative capacity was assessed through clonogenic assays. In addition, migration and invasion assays were conducted to evaluate the motility potential of the cells. Furthermore, the expression levels of Ki-67 and cleaved caspase-3 were analyzed by immunocytochemistry. Additionally, the cell cycle phase was evaluated in GBM cells using the Muse Cell Cycle Kit. Finally, in silico analyses were performed to predict the blood–brain barrier permeability of TAS-115 and its metabolites.

The half-maximal inhibitory concentration (IC₅₀) of TAS-115 was determined in GBM cells. Administration with TAS-115 and TMZ significantly reduced tumor cell proliferation (p<0.001). Moreover, the clonogenic potential of GBM cells was markedly suppressed (p<0.001). In addition, wound-healing assays demonstrated a significant attenuation of tumor cell migration, and Matrigel invasion assays further confirmed a substantial decrease in the invasive capacity of GBM cells (p<0.001). Furthermore, TAS-115 administration resulted in a reduction in Ki-67 protein expression, whereas the expression level of cleaved caspase-3 was increased, indicating enhanced apoptotic activity. Finally, in silico analyses revealed that 29 out of 32 identified metabolites of TAS-115 were predicted to cross the blood–brain barrier.

TAS-115 exhibits significant antitumor efficacy in TMZ-sensitive GBM models by inhibiting proliferation, clonogenic growth, migration, and invasion while enhancing apoptotic signaling. These findings support the therapeutic potential of TAS-115 in the treatment of GBM.

This study was supported by the Scientific and Technological Research Council of Türkiye (TÜBİTAK) (Grant no: 1001-123Z289).