The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models
Abstract Reovirus type 3 Dearing (RT3D) is an oncolytic, double-stranded RNA virus. To identify potential RT3D drug-viral sensitizer, here we use a high-throughput screen of therapeutic agents and find a PARP-1 inhibitor, talazoparib, as a top hit. RT3D interacts with retinoic acid-induced gene-1 (R...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61297-w |
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| author | Joan Kyula-Currie Victoria Roulstone James Wright Francesca Butera Arnaud Legrand Richard Elliott Martin McLaughlin Galabina Bozhanova Dragomir Krastev Stephen Pettitt Tencho Tenev Magnus Dillon Shane Foo Emmanuel C. Patin Victoria Jennings Charleen Chan Wah Hak Elizabeth Appleton Amarin Wongariyapak Malin Pedersen Antonio Rullan Jyoti Choudhary Chris Bakal Pascal Meier Christopher J. Lord Alan Melcher Kevin J. Harrington |
| author_facet | Joan Kyula-Currie Victoria Roulstone James Wright Francesca Butera Arnaud Legrand Richard Elliott Martin McLaughlin Galabina Bozhanova Dragomir Krastev Stephen Pettitt Tencho Tenev Magnus Dillon Shane Foo Emmanuel C. Patin Victoria Jennings Charleen Chan Wah Hak Elizabeth Appleton Amarin Wongariyapak Malin Pedersen Antonio Rullan Jyoti Choudhary Chris Bakal Pascal Meier Christopher J. Lord Alan Melcher Kevin J. Harrington |
| author_sort | Joan Kyula-Currie |
| collection | DOAJ |
| description | Abstract Reovirus type 3 Dearing (RT3D) is an oncolytic, double-stranded RNA virus. To identify potential RT3D drug-viral sensitizer, here we use a high-throughput screen of therapeutic agents and find a PARP-1 inhibitor, talazoparib, as a top hit. RT3D interacts with retinoic acid-induced gene-1 (RIG-I) and activates PARP-1, with consequent PARylation of components of the extrinsic apoptosis pathway. Pharmacological or genetic inhibition of PARP-1 abrogates this PARylation and enhances extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Interaction between PARP-1 and RIG-I induced by treating RT3D-infected cells with talazoparib activates downstream IFN-β and TNF/TRAIL production to amplify the therapeutic effect through positive feedback. Furthermore, the effect of RT3D-talazoparib combination is phenocopied by non-viral ds-RNA therapy and RIG-I agonism. In vivo, mouse tumour model results show that RT3D/talazoparib combination regimen induces complete control of inoculated tumour as well as protection from subsequent tumour rechallenge with the, with accompanied innate and adaptive immune activation. |
| format | Article |
| id | doaj-art-b9d6e4a2bc7545d692bb585d15d6a84e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b9d6e4a2bc7545d692bb585d15d6a84e2025-08-20T03:05:06ZengNature PortfolioNature Communications2041-17232025-07-0116111910.1038/s41467-025-61297-wThe PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse modelsJoan Kyula-Currie0Victoria Roulstone1James Wright2Francesca Butera3Arnaud Legrand4Richard Elliott5Martin McLaughlin6Galabina Bozhanova7Dragomir Krastev8Stephen Pettitt9Tencho Tenev10Magnus Dillon11Shane Foo12Emmanuel C. Patin13Victoria Jennings14Charleen Chan Wah Hak15Elizabeth Appleton16Amarin Wongariyapak17Malin Pedersen18Antonio Rullan19Jyoti Choudhary20Chris Bakal21Pascal Meier22Christopher J. Lord23Alan Melcher24Kevin J. Harrington25The Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins ResearchThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchThe CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins ResearchThe Institute of Cancer ResearchThe Institute of Cancer ResearchAbstract Reovirus type 3 Dearing (RT3D) is an oncolytic, double-stranded RNA virus. To identify potential RT3D drug-viral sensitizer, here we use a high-throughput screen of therapeutic agents and find a PARP-1 inhibitor, talazoparib, as a top hit. RT3D interacts with retinoic acid-induced gene-1 (RIG-I) and activates PARP-1, with consequent PARylation of components of the extrinsic apoptosis pathway. Pharmacological or genetic inhibition of PARP-1 abrogates this PARylation and enhances extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Interaction between PARP-1 and RIG-I induced by treating RT3D-infected cells with talazoparib activates downstream IFN-β and TNF/TRAIL production to amplify the therapeutic effect through positive feedback. Furthermore, the effect of RT3D-talazoparib combination is phenocopied by non-viral ds-RNA therapy and RIG-I agonism. In vivo, mouse tumour model results show that RT3D/talazoparib combination regimen induces complete control of inoculated tumour as well as protection from subsequent tumour rechallenge with the, with accompanied innate and adaptive immune activation.https://doi.org/10.1038/s41467-025-61297-w |
| spellingShingle | Joan Kyula-Currie Victoria Roulstone James Wright Francesca Butera Arnaud Legrand Richard Elliott Martin McLaughlin Galabina Bozhanova Dragomir Krastev Stephen Pettitt Tencho Tenev Magnus Dillon Shane Foo Emmanuel C. Patin Victoria Jennings Charleen Chan Wah Hak Elizabeth Appleton Amarin Wongariyapak Malin Pedersen Antonio Rullan Jyoti Choudhary Chris Bakal Pascal Meier Christopher J. Lord Alan Melcher Kevin J. Harrington The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models Nature Communications |
| title | The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models |
| title_full | The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models |
| title_fullStr | The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models |
| title_full_unstemmed | The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models |
| title_short | The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models |
| title_sort | parp inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models |
| url | https://doi.org/10.1038/s41467-025-61297-w |
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