PARP Inhibition potentiates boron neutron capture therapy in chemoresistant glioblastoma via DNA repair disruption

Glioblastoma (GBM) is the most aggressive primary brain tumor, with poor responsiveness to existing therapies and no established second-line treatment for recurrence. Boron neutron capture therapy (BNCT) has emerged as a promising modality that delivers selective cytotoxicity to recurrent GBM, yet its efficacy is constrained by tumor-intrinsic DNA repair mechanisms. Targeting DNA repair pathways may therefore represent a rational strategy to potentiate BNCT and improve outcomes in TMZ-resistant GBM. We investigated whether combining BPA-mediated BNCT with the PARP inhibitor olaparib enhances efficacy in temozolomide (TMZ)-resistant U-87 TR and parental U-87 MG GBM cells. Clonogenic assays were used to quantify cytotoxicity, while mechanistic studies evaluated DNA damage, cell cycle arrest, and apoptosis. Olaparib significantly sensitized GBM cells to BNCT, reducing survival to 40.7 ± 8.1% in U-87 MG and 24.2 ± 8.3% in U-87 TR cells, with radiation enhancement ratios of 1.53 and 1.95, respectively. In U-87 TR cells, the combination treatment induced persistent γH2AX foci, sustained G2/M arrest, and suppressed BNCT-driven upregulation of BRCA1 and RAD51, indicating impaired HR repair. Apoptosis was markedly increased in both cell lines, proceeding through PUMA–BAX activation in U-87 MG and via PUMA-independent pathways in U-87 TR. PARP inhibition (Olaparib) enhances BNCT-induced DNA damage, disrupts HR repair, and induces apoptosis through distinct mechanisms in sensitive and resistant GBM cells. These findings provide mechanistic evidence for BNCT–PARP inhibitor combinations as a strategy to overcome therapeutic resistance and merit further translational and clinical investigation in TMZ-resistant GBM.