PARP trapping enhances oncolytic Reovirus cell killing in melanoma


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Joan Kyula-Currie1,Victoria Roulstone2,Richard Elliot3,Stephen Pettitt3,Dragomir Krastev3,Holly Barker3,Martin McLaughlin3,Chris Lord3,Alan Melcher3,Kevin Harrington3
1Instiitute of Cancer Research,2Institute of Cancer Research,3Institute of cancer research

Abstract

Background

Oncolytic viruses have shown good potential in human clinical trials. Reovirus (RT3D), a naturally occurring human double stranded RNA oncolytic virus has shown preclinical efficacy in the treatment of a wide range of tumor types and reached phase III testing in clinical trials. Early clinical studies have shown that this agent has modest monotherapy efficacy and it has been used in combination regimens with cytotoxic chemotherapy. However, not all patients benefit from these treatments therefore highlighting a need to identify therapeutic opportunities for combining oncolytic viruses with other novel anti-cancer drugs.

Method

We carried out a screen containing a range of different targeted therapeutic agents including known cytotoxic drugs and some novel therapeutic agents with the aim of looking for potential “viral sensitizers” that could enhance RT3D tumor killing in the A375 BRAFV600E mutant melanoma cells. Cell Titer Glo was used as an endpoint assay to measure synergistic interaction between RT3D and the therapeutic agents

Results

We identified talazoparib (BMN-673), a potent PARP trapping poison as a top hit from the screen in A375 cells and validated our findings further in a panel of melanoma cell lines. RT3D infection induced PARP1 activation and this was abrogated in the presence of talazoparib or olaparib, another PARP poison. The combination of RT3D and the PARP poisons correlated with increased levels of cleaved caspase 3, cleaved casapse 8 and PARP cleavage compared to either agent alone. In addition, we found PARP1 to be trapped in the chromatin following RT3D and talazoparib and olaparib. Finally, there was synthetic lethality in cells defective in the DNA binding domain of PARP1 compared to wild type PARP1

Conclusion

Our pre-clinical data provide a strong rationale for the combination of RT3D with PARP1 trapping agents in melanoma and potentially other tumors

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