PARP（聚合酶-ADP核糖）抑制剂在多个同源重组（HR）缺陷肿瘤中展示了很大的临床活性。然而，对于胶质母细胞瘤（GBM）患者，单独使用PARP抑制剂的效果并不明显。当PARP抑制剂与其他治疗药物联合使用时，显示出相当大的潜力。因此，新的联合疗法可能提高PARP抑制剂的疗效，并克服GBM中的抗药机制。在本研究中，我们报道了PARP抑制剂奥拉帕尼布和XPO1（exportin 1）抑制剂KPT330同时治疗对GBM细胞具有协同的抗癌效应。机制上，我们显示KPT330在细胞核中诱导SQSTM1（sequestosome 1）的核滞留，并进一步抑制了奥拉帕尼布介导的DNA修复信号H2AX（H2A.X变异组蛋白）的泛素化作用，从而抑制了GBM中的DNA损伤应答和修复。此外，在细胞质中，KPT330阻断了奥拉帕尼布药剂引起的自噬通路的激活，降低了LAPTM4B（溶酶体蛋白质跨膜4 beta）的表达，并诱导溶酶体功能障碍，从而阻止了自噬体的降解，最终促进细胞死亡。此外，在LN229-luc小鼠正位移植模型中，联合治疗显示出明显增强的抗肿瘤疗效，与单药疗法相比。这些数据说明了奥拉帕尼布和KPT330联合口服治疗胶质母细胞瘤的应用前景。

PARP (poly(ADP-ribose) polymerase) inhibitors have demonstrated promising clinical activity in multiple homologous recombination (HR) deficiency tumors. However, glioblastoma (GBM) patients have obtained little benefit from PARP inhibitors alone. PARP inhibition shows considerable promise when used together with other therapeutic agents. Thus, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms in GBM. Herein, we report that concurrent treatment with the PARP inhibitor olaparib and XPO1 (exportin 1) inhibitor KPT330 showed synergetic anticancer effects on GBM cells. Mechanistically, in the nucleus, we show that KPT330 induced the nuclear retention of SQSTM1 (sequestosome 1) and further inhibited the ubiquitination of the DNA repair signal H2AX (H2A.X variant histone) mediated by olaparib, thus inhibiting DNA damage response and repair in GBM. Moreover, in the cytoplasm, KPT330 blocked the activation of autophagic flux caused by olaparib reagent, downregulated the expression of LAPTM4B (lysosomal protein transmembrane 4 beta) and induced the dysfunction of lysosomes, thereby preventing the degradation of autophagosome, and ultimately promoted cell death. Furthermore, in the LN229-luc mouse orthotopic xenograft model, combination treatment showed significantly increased antitumor efficacy compared to each monotherapy. These data illustrate the application prospects of combined oral administration of olaparib and KPT330 for the treatment of glioblastoma.