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Supplementary Data from CDK4/6 Inhibition Enhances Oncolytic Virus Efficacy by Potentiating Tumor-Selective Cell Killing and T-cell Activation in Refractory Glioblastoma

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posted on 2023-03-31, 05:21 authored by Jingshu Xiao, Jiaming Liang, Junjie Fan, Panpan Hou, Xiaodong Li, Haipeng Zhang, Kai Li, Lang Bu, Ping Li, Miao He, Yongheng Zhong, Liping Guo, Penghui Jia, Qiaoqiao Xiao, Junyu Wu, Hong Peng, Chunmei Li, Fan Xing, Deyin Guo
Supplementary Data from CDK4/6 Inhibition Enhances Oncolytic Virus Efficacy by Potentiating Tumor-Selective Cell Killing and T-cell Activation in Refractory Glioblastoma

Funding

Shenzhen Science and Technology Program

National Natural Science Foundation of China

Natural Science Foundation of Guangdong Province

Shenzhen Scientific and Technological Innovation Talents Project

Guangdong Zhujiang Talents Program

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ARTICLE ABSTRACT

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. This study proposes inhibition of cyclin-dependent kinases as a clinically translatable combinatorial strategy to enhance the efficacy of oncolytic virotherapy in GBM.

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