Sequential Inhibition of PARP and BET as a Rational Therapeutic Strategy for Glioblastoma

PARP inhibitors (PARPi) show significant potential for treating glioblastoma (GBM), but their widespread use has been limited by adverse effects. Recent unbiased transcriptomic and proteomic sequencing has revealed that the BET inhibitor (BETi) Birabresib profoundly impacts DNA replication and cell cycle progression in GBM cells, extending beyond the previously known effects of BET inhibition on homologous recombination repair. In vitro studies using established GBM cell lines and patient-derived primary GBM cells, along with in vivo experiments involving orthotopic tumor models in zebrafish and nude mice, demonstrate that combining PARPi with BETi achieves a synergistic inhibition of GBM. Notably, DNA damage persists even after stopping PARPi monotherapy, suggesting that a sequential approach—administering PARPi followed by BETi—can sustain antitumor activity while minimizing toxicity. In GBM cells with high baseline replication stress, this sequential regimen provides similar efficacy to concurrent treatment, while also shielding normal glial cells with lower replication stress from DNA damage and subsequent cell death. This study offers strong preclinical support for developing novel drug administration strategies that leverage PARPi in GBM treatment.