The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism
Reovirus 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 kina...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-03-01
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| Series: | Molecular Therapy: Oncolytics |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770520300073 |
| _version_ | 1818038872198610944 |
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| author | Martin McLaughlin Malin Pedersen Victoria Roulstone Katharina F. Bergerhoff Henry G. Smith Harriet Whittock Joan N. Kyula Magnus T. Dillon Hardev S. Pandha Richard Vile Alan A. Melcher Kevin J. Harrington |
| author_facet | Martin McLaughlin Malin Pedersen Victoria Roulstone Katharina F. Bergerhoff Henry G. Smith Harriet Whittock Joan N. Kyula Magnus T. Dillon Hardev S. Pandha Richard Vile Alan A. Melcher Kevin J. Harrington |
| author_sort | Martin McLaughlin |
| collection | DOAJ |
| description | Reovirus 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. Keywords: reovirus type 3 Dearing, Reolysin, pelareorep, PERK, unfolded protein response, integrated stress response, ER stress, oncolytic virus, ATF4 |
| first_indexed | 2024-12-10T07:49:38Z |
| format | Article |
| id | doaj.art-ea1817def2d74912aacb316306d0be16 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-10T07:49:38Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-ea1817def2d74912aacb316306d0be162022-12-22T01:57:04ZengElsevierMolecular Therapy: Oncolytics2372-77052020-03-0116238249The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent MechanismMartin McLaughlin0Malin Pedersen1Victoria Roulstone2Katharina F. Bergerhoff3Henry G. Smith4Harriet Whittock5Joan N. Kyula6Magnus T. Dillon7Hardev S. Pandha8Richard Vile9Alan A. Melcher10Kevin J. Harrington11The Institute of Cancer Research, London, UK; Corresponding author: Martin McLaughlin, The Institute of Cancer Research, London, UK.The Institute of Cancer Research, London, UKThe Institute of Cancer Research, London, UKThe Institute of Cancer Research, London, UKThe Institute of Cancer Research, London, UKThe Institute of Cancer Research, London, UKThe Institute of Cancer Research, London, UKThe Institute of Cancer Research, London, UKUniversity of Surrey, Guildford, UKMayo Clinic, Rochester, MN, USAThe Institute of Cancer Research, London, UKThe Institute of Cancer Research, London, UKReovirus 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. Keywords: reovirus type 3 Dearing, Reolysin, pelareorep, PERK, unfolded protein response, integrated stress response, ER stress, oncolytic virus, ATF4http://www.sciencedirect.com/science/article/pii/S2372770520300073 |
| spellingShingle | Martin McLaughlin Malin Pedersen Victoria Roulstone Katharina F. Bergerhoff Henry G. Smith Harriet Whittock Joan N. Kyula Magnus T. Dillon Hardev S. Pandha Richard Vile Alan A. Melcher Kevin J. Harrington The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism Molecular Therapy: Oncolytics |
| title | The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism |
| title_full | The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism |
| title_fullStr | The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism |
| title_full_unstemmed | The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism |
| title_short | The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism |
| title_sort | perk inhibitor gsk2606414 enhances reovirus infection in head and neck squamous cell carcinoma via an atf4 dependent mechanism |
| url | http://www.sciencedirect.com/science/article/pii/S2372770520300073 |
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