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Mechanisms of therapeutic synergy between pattern recognition response agonists and cdk4 inhibitors

ABSTRACT: Cytoplasmic nucleic acid sensors for double-stranded (ds) RNA (RIG-I/MDA5) and DNA (cGAS-STING) are pattern recognition receptors (PRRs) key to intracellular anti-viral responses. Recent research has highlighted roles for PRR agonists, including oncolytic virotherapy agents, in anti-tumor immunotherapy. Reovirus type 3 Dearing (Rt3D) is an oncolytic dsRNA virus with limited single-agent activity in clinical studies, but potential for use in combination regimens. We sought synergistic drug-virotherapy combinations using an unbiased screening approach that highlighted the CDK4/6 inhibitor, palbociclib, as a leading hit. We found that, when combined with Rt3D, palbociclib augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) signaling. Combined Rt3D-palbociclib treatment potently increased interferon signaling and endogenous retroviral transcripts. Knockdown (siRNA) studies indicated key UPR proteins and the RNA sensor, RIG-I, were essential to the phenotype observed. Mechanistically independent experiments, using canonical RIG-I agonists and the ER stress inducer (thapsigargin), confirmed cross-talk between RNA sensing and ER stress pathways that augment cancer cell death and interferon production. Combined Rt3D-palbociclib increased innate immune activation and effector function. Our findings demonstrate that UPR signaling and innate immune RNA sensor crosstalk can be exploited to enhance anti-cancer efficacy with pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, as well as broadening the therapeutic remit of CDK4/6 inhibitors to include their role as ER stress sensitizers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD022642 | Pride | 2026-06-22

REPOSITORIES: Pride

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	Lumos50cm_VR01TMT11plex-A01.raw	Raw
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	Lumos50cm_VR01TMT11plex-A05.raw	Raw

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Project description:Oncolytic Reovirus type 3 Dearing (RT3D), is a naturally occurring double-stranded (ds) RNA virus that is under development as an oncolytic immunotherapy We used an unbiased high-throughput cytotoxicity screen of different targeted therapeutic agents with the aim of identifying potential drug-viral sensitizers to enhance RT3D tumour killing. Talazoparib, a clinical poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor, was identified as a top hit and found to cause profound sensitisation to RT3D. This effect was not seen with other classes of oncolytic virus and was not mediated by enhanced viral replication or PARP inhibitor-related effects on the DNA damage response. 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 and genetic inhibition of PARP-1 abrogates this PARylation and increases levels of extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Direct interaction between PARP-1 and RIG-I following RT3D/talazoparib treatment is a key factor in activating downstream signaling pathways that lead to IFN- and TNF-/TRAIL production which, in turn, amplify the therapeutic effect through positive feedback. Critically, it was possible to phenocopy the effect of RT3D through the use of non-viral ds-RNA therapy and RIG-I agonism. In in vivo studies, we demonstrated profound combinatorial efficacy of RT3D and talazoparib in human A375 melanoma in immunodeficient mice. More impressively, in immunocompetent mouse models of 4434 murine melanoma, we achieved 100% tumour control and protection from subsequent tumour rechallenge with the combination regimen. Correlative immunophenotyping confirmed significant innate and adaptive immune activation with the combination of RT3D and PARP inhibition. Taken together, these data provide a clear line of sight to clinical translation of combined regimens of PARP inhibition or ds-RNA agonism, with either viral or non-viral agents, in tumour types beyond the relatively narrow confines of current licensed indications for PARP inhibition.

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Mechanisms of therapeutic synergy between pattern recognition response agonists and cdk4 inhibitors

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