Glioblastoma (GBM) is among the most aggressive human cancers. Although oncolytic virus (OV) therapy has been proposed as a potential approach to treat GBM, it frequently fails because GBM cells are usually nonpermissive to OV. Here, we describe a dual-step drug screen for identifying chemical enhancers of OV in GBM. From a high-throughput screen of 1416 FDA-approved drugs, an inhibitor of CDK4/6 was identified as the top enhancer, selectively increasing potency of two OV strains, VSVΔ51 and Zika virus. Mechanistically, CDK4/6 inhibition promoted autophagic degradation of MAVS, resulting in impaired antiviral responses and enhanced tumor-selective replication of VSVΔ51 in vitro and in vivo. CDK4/6 inhibition cooperated with VSVΔ51 to induce severe DNA damage stress and amplify oncolysis. In GBM xenograft models, combined treatment with CDK4/6 inhibitor and VSVΔ51 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice. Further investigation revealed that CDK4/6 inhibitor and VSVΔ51 synergistically induced immunogenic cell death and boosted antitumor immunity. Together, this study features a promising approach of treating aggressive GBM through the combination of CDK4/6 inhibitor with OV. Significance: This study proposes inhibition of cyclin-dependent kinases as a clinically translatable combinatorial strategy to enhance the efficacy of oncolytic virotherapy in GBM.

中文翻译：

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CDK4/6 抑制通过增强难治性胶质母细胞瘤中肿瘤选择性细胞杀伤和 T 细胞激活来增强溶瘤病毒功效

胶质母细胞瘤（GBM）是最具侵袭性的人类癌症之一。尽管溶瘤病毒 (OV) 疗法已被提议作为治疗 GBM 的潜在方法，但它经常失败，因为 GBM 细胞通常不允许 OV。在这里，我们描述了一种双步药物筛选，用于识别 GBM 中 OV 的化学增强剂。通过对 1416 种 FDA 批准的药物进行高通量筛选，CDK4/6 抑制剂被确定为最佳增强剂，可选择性增强两种 OV 病毒株（VSVΔ51 和寨卡病毒）的效力。从机制上讲，CDK4/6抑制促进了MAVS的自噬降解，导致抗病毒反应受损并增强了VSVΔ51在体外和体内的肿瘤选择性复制。CDK4/6 抑制与 VSVΔ51 协同诱导严重的 DNA 损伤应激并放大溶瘤作用。在 GBM 异种移植模型中，CDK4/6抑制剂和VSVΔ51联合治疗显着抑制肿瘤生长并延长荷瘤小鼠的生存期。进一步研究表明，CDK4/6 抑制剂和 VSVΔ51 协同诱导免疫原性细胞死亡并增强抗肿瘤免疫力。总之，这项研究提出了一种通过 CDK4/6 抑制剂与 OV 联合治疗侵袭性 GBM 的有前景的方法。意义：本研究提出抑制细胞周期蛋白依赖性激酶作为一种临床可转化的组合策略，以增强 GBM 溶瘤病毒疗法的疗效。这项研究提出了一种通过 CDK4/6 抑制剂与 OV 联合治疗侵袭性 GBM 的有前途的方法。意义：本研究提出抑制细胞周期蛋白依赖性激酶作为一种临床可转化的组合策略，以增强 GBM 溶瘤病毒疗法的疗效。这项研究提出了一种通过 CDK4/6 抑制剂与 OV 联合治疗侵袭性 GBM 的有前途的方法。意义：本研究提出抑制细胞周期蛋白依赖性激酶作为一种临床可转化的组合策略，以增强 GBM 溶瘤病毒疗法的疗效。