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dc.contributor.authorMcLaughlin, M
dc.contributor.authorPedersen, M
dc.contributor.authorRoulstone, V
dc.contributor.authorBergerhoff, KF
dc.contributor.authorSmith, HG
dc.contributor.authorWhittock, H
dc.contributor.authorKyula, JN
dc.contributor.authorDillon, MT
dc.contributor.authorPandha, HS
dc.contributor.authorVile, R
dc.contributor.authorMelcher, AA
dc.contributor.authorHarrington, KJ
dc.date.accessioned2020-01-27T13:09:45Z
dc.date.issued2020-03
dc.identifier.citationMolecular therapy oncolytics, 2020, 16 pp. 238 - 249
dc.identifier.issn2372-7705
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3496
dc.identifier.eissn2372-7705
dc.identifier.doi10.1016/j.omto.2020.01.001
dc.description.abstractReovirus type 3 Dearing (reovirus) is a tumor-selective oncolytic virus currently under evaluation in clinical trials. Here, we report that the therapeutic efficacy of reovirus in head and neck squamous cell cancer can be enhanced by targeting the unfolded protein response (UPR) kinase, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). PERK inhibition by GSK2606414 increased reovirus efficacy in both 2D and 3D models in vitro, while perturbing the normal host cell response to reovirus-induced endoplasmic reticulum (ER) stress. UPR reporter constructs were used for live-cell 3D spheroid imaging. Profiling of eIF2a-ATF4, IRE1a-XBP1, and ATF6 pathway activity revealed a context-dependent increase in eIF2a-ATF4 signaling due to GSK2606414. GSK2606414 blocked eIF2a-ATF4 signaling because of the canonical ER stress agent thapsigargin. In the context of reovirus infection, GSK2606414 induced eIF2a-ATF4 signaling. Knockdown of eIF2a kinases PERK, GCN2, and PKR revealed eIF2a-ATF4 reporter activity was dependent on either PERK or GCN2. Knockdown of ATF4 abrogated the GSK2606414-induced increase in reovirus protein levels, confirming eIF2a-ATF signaling as key to the observed phenotype. Our work identifies a novel approach to enhance the efficacy and replication of reovirus in a therapeutic setting.
dc.formatElectronic-eCollection
dc.format.extent238 - 249
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleThe PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism.
dc.typeJournal Article
dcterms.dateAccepted2020-01-02
rioxxterms.versionofrecord10.1016/j.omto.2020.01.001
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular therapy oncolytics
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.publication-statusPublished
pubs.volume16
pubs.embargo.termsNo embargo
icr.researchteamTargeted Therapyen_US
icr.researchteamTranslational Immunotherapyen_US
dc.contributor.icrauthorMcLaughlin, Martinen
dc.contributor.icrauthorHarrington, Kevinen
dc.contributor.icrauthorDillon, Magnusen
dc.contributor.icrauthorMelcher, Alanen
dc.contributor.icrauthorPedersen, Malinen


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