| Autor: |
Zhou X; Shenzhen International Institute for Biomedical Research, Shenzhen 518110, China., Zhao J; Shenzhen International Institute for Biomedical Research, Shenzhen 518110, China., Zhang JV; Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Wu Y; Department of Immunology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China., Wang L; Department of Immunology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China., Chen X; Shenzhen International Institute for Biomedical Research, Shenzhen 518110, China., Ji D; Department of Medical Oncology, Shanghai Cancer Center and Shanghai Medical College, Fudan University, Shanghai 200032, China., Zhou GG; Shenzhen International Institute for Biomedical Research, Shenzhen 518110, China. |
| Abstrakt: |
Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and kill tumor cells with naturally inherited or engineered properties. Considering the limitations of OVs monotherapy, combination therapy has been widely explored. MEK inhibitor (MEKi) Trametinib is an FDA-approved kinase inhibitor indicated for the treatment of tumors with BRAF V600E or V600K mutations. In this study, the oncolytic activity in vitro and anti-tumor therapeutic efficacy in vivo when combined with oHSV and MEKi Trametinib were investigated. We found: (1) Treatment with MEKi Trametinib augmented oHSV oncolytic activity in BRAF V600E-mutated tumor cells. (2) Combination treatment with oHSV and MEKi Trametinib enhanced virus replication mediated by down-regulation of STAT1 and PKR expression or phosphorylation in BRAF V600E-mutated tumor cells as well as BRAF wt/KRAS-mutated tumor cells. (3) A remarkably synergistic therapeutic efficacy was shown in vivo for BRAF wt/KRAS-mutated tumor models, when a combination of oHSV including PD-1 blockade and MEK inhibition. Collectively, these data provide some new insights for clinical development of combination therapy with oncolytic virus, MEK inhibition, and checkpoint blockade for BRAF or KRAS-mutated tumors. |
