Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Mol Ther. 2023 Nov 1;31(11):3176-3192. doi: 10.1016/j.ymthe.2023.09.017. Epub 2023 Sep 27.
The clinical efficacy of VSVΔ51 oncolytic virotherapy has been limited by tumor resistance to viral infection, so strategies to transiently repress antiviral defenses are warranted. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor currently being tested in clinical trials for its antitumor potential. In this study, we demonstrate that pevonedistat sensitizes human and murine cancer cells to increase oncolytic VSVΔ51 infection, increase tumor cell death, and improve therapeutic outcomes in resistant syngeneic murine cancer models. Increased VSVΔ51 infectivity was also observed in clinical human tumor samples. We further identify the mechanism of this effect to operate via blockade of the type 1 interferon (IFN-1) response through neddylation-dependent interferon-stimulated growth factor 3 (ISGF3) repression and neddylation-independent inhibition of NF-κB nuclear translocation. Together, our results identify a role for neddylation in regulating the innate immune response and demonstrate that pevonedistat can improve the therapeutic outcomes of strategies using oncolytic virotherapy.
VSVΔ51 溶瘤病毒治疗的临床疗效受到肿瘤对病毒感染的抵抗限制，因此有必要采用暂时抑制抗病毒防御的策略。Pevonedistat 是一种首创的 NEDD8 激活酶 (NAE) 抑制剂，目前正在临床试验中测试其抗肿瘤潜力。在这项研究中，我们证明了 pevonedistat 可增强人类和鼠类癌细胞对溶瘤性 VSVΔ51 感染的敏感性，增加肿瘤细胞死亡，并改善耐药同源鼠类癌症模型的治疗效果。在临床人类肿瘤样本中也观察到了增加的 VSVΔ51 感染力。我们进一步确定了这种作用的机制是通过抑制干扰素刺激基因 3 (ISGF3) 的 neddylation 依赖性和 NF-κB 核易位的 neddylation 独立性来阻断 I 型干扰素 (IFN-1) 反应。总之，我们的研究结果确定了 neddylation 在调节先天免疫反应中的作用，并证明了 pevonedistat 可以提高使用溶瘤病毒治疗策略的治疗效果。
