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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Joan Kyula-Currie & Victoria Roulstone & James Wright & Francesca Butera & Arnaud Legrand & Richard Elliott & Martin McLaughlin & Galabina Bozhanova & Dragomir Krastev & Stephen Pettitt & Tencho Tenev, 2025. "The PARP inhibitor talazoparib synergizes with reovirus to induce cancer killing and tumour control in vivo in mouse models," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61297-w
    DOI: 10.1038/s41467-025-61297-w
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