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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月8日

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  • 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

摘要

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.