Talazoparib Interacts With Oncolytic Reovirus To Enhance Death-Inducing Signaling Complex (Disc)-Mediated Apoptosis And Immune Response.

Abstract Reovirus (RT3D) is a naturally occurring double-stranded RNA oncolytic virus that has shown preclinical efficacy in a wide range of tumor types. Early phase clinical studies have shown that this agent has modest monotherapy efficacy and can safely be combined with cytotoxic chemotherapy regimens. In the current studies, we used a high-throughput drug screen approach of different targeted therapeutic agents with the aim of looking for potential viral sensitizers that could enhance RT3D tumor killing. BMN-673 (talazoparib), a clinically approved poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor was identified as a top hit and found to sensitize profoundly to RT3D both in vitro and in vivo in human xenograft tumors in a nude mouse model. We found that RT3D activated cellular PARP1 and was associated with PARylation of cellular proteins, including components of the DISC-associated cell death machinery. Combined treatment with RT3D and talazoparib enhanced extrinsic apoptosis (amplified by autocrine/paracrine TNF-α and TRAIL signaling), NF-κB pathway activity and pro-inflammatory cytokine production (CCL5/RANTES, CXCL8/IL8, CXCL1/GRO and CXCL10/IP10). Signaling was shown to be dependent on nucleic acid sensing mechanisms mediated by RIG-I and TLR3. We also found anti-tumour efficacy in an immunocompetent mouse model and this correlated with an increase in an immune response following combination treatment of RT3D and talazoparib. Our data provide a strong rationale for the combination of oncolytic RT3D with PARP1 inhibitors to exploit immunogenic response in cancer treatment. Citation Format: Joan N. Kyula, Victoria Roulstone, Richard Elliott, Harriet Whittock, Galabina Bozhanova, Martin McLaughlin, Malin Pedersen, Dragomir Krastev, Stephen Pettitt, Arnaud Legrand, Tencho Tenev, James Wright, Lu Yu, Jyoti Choudhary, Pascal Meier, Christopher J. Lord, Alan Melcher, Grey Wilkinson, Matt Coffey, Kevin J. Harrington. Talazoparib interacts with oncolytic reovirus to enhance death-inducing signaling complex (DISC)-mediated apoptosis and immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1932.