The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models

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 and Kevin J. Harrington
Additional contact information
Joan Kyula-Currie: The Institute of Cancer Research
Victoria Roulstone: The Institute of Cancer Research
James Wright: The Institute of Cancer Research
Francesca Butera: The Institute of Cancer Research
Arnaud Legrand: The Institute of Cancer Research
Richard Elliott: The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research
Martin McLaughlin: The Institute of Cancer Research
Galabina Bozhanova: The Institute of Cancer Research
Dragomir Krastev: The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research
Stephen Pettitt: The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research
Tencho Tenev: The Institute of Cancer Research
Magnus Dillon: The Institute of Cancer Research
Shane Foo: The Institute of Cancer Research
Emmanuel C. Patin: The Institute of Cancer Research
Victoria Jennings: The Institute of Cancer Research
Charleen Chan Wah Hak: The Institute of Cancer Research
Elizabeth Appleton: The Institute of Cancer Research
Amarin Wongariyapak: The Institute of Cancer Research
Malin Pedersen: The Institute of Cancer Research
Antonio Rullan: The Institute of Cancer Research
Jyoti Choudhary: The Institute of Cancer Research
Chris Bakal: The Institute of Cancer Research
Pascal Meier: The Institute of Cancer Research
Christopher J. Lord: The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research
Alan Melcher: The Institute of Cancer Research
Kevin J. Harrington: The Institute of Cancer Research

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61297-w

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