PDF(Pubmed)
Abstract：
PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient-derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy.
摘要：
PARP抑制剂（PARPi）在治疗胶质母细胞瘤（GBM）方面具有重要的前景。然而,不利影响限制了其广泛应用。通过无偏转录组和蛋白质组测序，发现BET抑制剂（BETi）Birabresib深刻地改变了GBM细胞中DNA复制和细胞周期进程的过程，超出了先前报道的BET抑制对同源重组修复的影响。通过使用已建立的GBM细胞系和患者来源的原代GBM细胞的体外实验，以及斑马鱼和裸鼠体内原位移植肿瘤实验，证明PARPi和BETi的同时给药可以协同抑制GBM。有趣的是，观察到PARPi单一疗法停药后DNA损伤仍存在，这意味着PARPi和BETi的顺序给药可以保持抗肿瘤功效，同时降低毒性。在基线复制应激升高的GBM细胞中，序贯方案表现出与同期治疗相当的疗效，保护具有较低基线复制应激的正常神经胶质细胞免受DNA毒性和随后的死亡。这项研究提供了令人信服的临床前证据，支持针对GBM治疗的PARPi创新药物管理策略的开发。
