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Synthetic lethality of PARP inhibition in BRCA-network disrupted tumor cells is associated with interferon pathway activation and enhanced by interferon-γ

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Abstract

Tumor suppressor genes BRCA1 and BRCA2 function in a complex gene network that regulates homologous recombination and DNA double-strand break repair. Disruption of the BRCA-network through gene mutation, deletion, or RNAi-mediated silencing can sensitize cells to small molecule inhibitors of poly (ADP-ribose) polymerase (PARPi). Here, we demonstrate that BRCA-network disruption in the presence of PARPi leads to the selective induction and enhancement of interferon pathway and apoptotic gene expression in cultured tumor cells. In addition, we report PARPi cytotoxicity in BRCA1-deficient tumor cells is enhanced >10-fold when combined with interferon-γ. These findings establish a link between synthetic lethality of PARPi in BRCA-network disrupted cells and interferon pathway activation triggered by genetic instability.

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Acknowledgments

We wish to thank our colleagues at Rosetta and Merck for support and stimulating discussions. We thank Kenzie MacIsaac for help with GO annotation of PARPi signature gene lists. We thank Jim Roberts, David Wiest, and Brett Kaiser for critical reading of this manuscript. The authors state that there exists no conflict of interest with the publication of this manuscript.

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Authors and Affiliations

  1. Rosetta Inpharmatics LLC, A Wholly Owned Subsidiary of Merck & Co., Inc, Seattle, WA, 98109, USA

    Paul Warrener, Sammy Kim, Matthew Biery, Marcia Gordon, Peter S. Linsley & Michael Carleton

  2. Merck Research Laboratories, Boston, MA, 02115, USA

    Sybil M. G. Williams & Carlo Toniatti

  3. Merck & Co., Inc, West Point, PA, 19486, USA

    Michele A. Cleary

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  1. Paul Warrener
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Correspondence to Michael Carleton.

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Warrener, P., Kim, S., Williams, S.M.G. et al. Synthetic lethality of PARP inhibition in BRCA-network disrupted tumor cells is associated with interferon pathway activation and enhanced by interferon-γ. Apoptosis 17, 691–701 (2012). https://doi.org/10.1007/s10495-012-0707-4

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  • DOI: https://doi.org/10.1007/s10495-012-0707-4

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