Abstract LB537: CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Although oncolytic virus (OV) therapy has been proposed as a potential approach to treat GBM, the resistance is frequently observed because GBM cells are usually nonpermissive to OV. Here, we describe a dual-step drug screen for identifying chemical enhancers of oncolytic virus in GBM. An inhibitor of the cyclin-dependent kinases 4/6 (CDK4/6) was identified as the top enhancer from 1416 FDA-approved drugs, selectively increasing potency of the two OV strains, including VSVΔ51 and Zika virus. Mechanistically, CDK4/6 inhibition promoted the 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, leading to the amplification of oncolysis. In GBM xenograft models, combination treatment of CDK4/6 inhibitor and VSVΔ51 significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice. Further investigation revealed that CDK4/6 inhibitor and VSVΔ51 synergistically induced the immunogenic cell death and boosted the anti-tumor immunity. Together, our study features a promising approach of treating aggressive GBM through the combination of CDK4/6 inhibitor with OV. Citation Format: Deyin Guo, Fan Xing, Jingshu Xiao, Jiaming liang. CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB537.