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联合 MEK 抑制剂曲美替尼增强溶瘤单纯疱疹病毒在某些 BRAF 或 KRAS 突变结直肠癌或肺癌模型中的治疗效果。

Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus with MEK Inhibitor Trametinib in Some BRAF or KRAS-Mutated Colorectal or Lung Carcinoma Models.

机构信息

Shenzhen International Institute for Biomedical Research, Shenzhen 518110, China.

Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.

出版信息

Viruses. 2021 Sep 3;13(9):1758. doi: 10.3390/v13091758.

DOI:10.3390/v13091758
PMID:34578339
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8473197/
Abstract

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.

摘要

溶瘤病毒（OV）作为一种有前途的治疗剂，可以选择性地感染和杀死具有天然遗传或工程特性的肿瘤细胞。鉴于 OV 单药治疗的局限性，联合治疗已被广泛探索。MEK 抑制剂（MEKi）曲美替尼是一种获得 FDA 批准的激酶抑制剂，用于治疗具有 BRAF V600E 或 V600K 突变的肿瘤。在这项研究中，研究了与 oHSV 和 MEKi 曲美替尼联合使用时的体外溶瘤活性和体内抗肿瘤治疗效果。我们发现：（1）MEKi 曲美替尼处理增强了 BRAF V600E 突变肿瘤细胞中的 oHSV 溶瘤活性。（2）oHSV 和 MEKi 曲美替尼联合治疗通过下调 STAT1 和 PKR 表达或磷酸化增强了 BRAF V600E 突变肿瘤细胞以及 BRAF wt/KRAS 突变肿瘤细胞中的病毒复制。（3）在 BRAF wt/KRAS 突变肿瘤模型中，当 oHSV 联合 PD-1 阻断和 MEK 抑制时，体内显示出显著的协同治疗效果。总的来说，这些数据为临床开发联合治疗提供了一些新的见解，包括溶瘤病毒、MEK 抑制和针对 BRAF 或 KRAS 突变的肿瘤的检查点阻断。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/66840ab50381/viruses-13-01758-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/c8a967fc8382/viruses-13-01758-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/e15c072a6b46/viruses-13-01758-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/17404f31303f/viruses-13-01758-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/f0b15723a244/viruses-13-01758-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/b912b6eef271/viruses-13-01758-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/66840ab50381/viruses-13-01758-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/c8a967fc8382/viruses-13-01758-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/e15c072a6b46/viruses-13-01758-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/17404f31303f/viruses-13-01758-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/f0b15723a244/viruses-13-01758-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/b912b6eef271/viruses-13-01758-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7aa/8473197/66840ab50381/viruses-13-01758-g006.jpg

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