Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, sensitizes cancer cells to VSVΔ51 oncolytic virotherapy.
cancer
innate immunity
interferon
neddylation
oncolytic virotherapy
pevonedistat
viral enhancement
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
01 11 2023
01 11 2023
Historique:
received:
06
06
2023
revised:
23
08
2023
accepted:
23
09
2023
pmc-release:
01
11
2024
medline:
6
11
2023
pubmed:
28
9
2023
entrez:
28
9
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37766429
pii: S1525-0016(23)00504-X
doi: 10.1016/j.ymthe.2023.09.017
pmc: PMC10638453
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Interferons
9008-11-1
NEDD8 Protein
0
NEDD8 protein, human
0
pevonedistat
S3AZD8D215
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3176-3192Subventions
Organisme : CIHR
ID : INI-147824
Pays : Canada
Organisme : CIHR
ID : 705952
Pays : Canada
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests B.W., A.B., R.A., and J.-S.D. are co-inventors on a patent covering the use of NAE inhibitors as an enhancer of RNA viruses.
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