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PARP-1 inhibition with or without ionizing radiation confers reactive oxygen species-mediated cytotoxicity preferentially to cancer cells with mutant TP53

Oncogene volume 37, pages 2793–2805 (2018)Cite this article

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Abstract

Biomarkers and mechanisms of poly (ADP-ribose) polymerase (PARP) inhibitor-mediated cytotoxicity in tumor cells lacking a BRCA-mutant or BRCA-like phenotype are poorly defined. We sought to explore the utility of PARP-1 inhibitor (PARPi) treatment with/without ionizing radiation in muscle-invasive bladder cancer (MIBC), which has poor therapeutic outcomes. We assessed the DNA damaging and cytotoxic effects of the PARPi olaparib in nine bladder cancer cell lines. Olaparib radiosensitized all cell lines with dose enhancement factors from 1.22 to 2.27. Radiosensitization was correlated with the induction of potentially lethal DNA double-strand breaks (DSB) but not with RAD51 foci formation. The ability of olaparib to radiosensitize MIBC cells was linked to the extent of cell kill achieved with the drug alone. Unexpectedly, increased levels of reactive oxygen species (ROS) resulting from PARPi treatment were the cause of DSB throughout the cell cycle in vitro and in vivo. ROS originated from mitochondria and were required for the radiosensitizing effects of olaparib. Consistent with the role of TP53 in ROS regulation, loss of p53 function enhanced radiosensitization by olaparib in non-isogenic and isogenic cell line models and was associated with increased PARP-1 expression in bladder cancer cell lines and tumors. Impairment of ATM in addition to p53 loss resulted in an even more pronounced radiosensitization. In conclusion, ROS suppression by PARP-1 in MIBC is a potential therapeutic target either for PARPi combined with radiation or drug alone treatment. The TP53 and ATM genes, commonly mutated in MIBC and other cancers, are candidate biomarkers of PARPi-mediated radiosensitization.

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Acknowledgements

Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center (J. A. Efstathiou, H. Willers), UK Wellcome Trust 102696 (C.H. Benes).

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Authors and Affiliations

  1. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Qi Liu, Liliana Gheorghiu, Michael Drumm, Rebecca Clayman, Alec Eidelman, Meng Wang, Lynnette Marcar, Jason A. Efstathiou & Henning Willers

  2. Department of Radiation Oncology, University of California, San Francisco, CA, USA

    Qi Liu

  3. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Matthew F. Wszolek, Aria Olumi & Adam Feldman

  4. Radiation Oncology Branch, Center for Cancer Research, NIH, Bethesda, MD, USA

    Deborah E. Citrin

  5. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Chin-Lee Wu

  6. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Cyril H. Benes

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These authors contributed equally: Jason A. Efstathiou and Henning Willers.

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Liu, Q., Gheorghiu, L., Drumm, M. et al. PARP-1 inhibition with or without ionizing radiation confers reactive oxygen species-mediated cytotoxicity preferentially to cancer cells with mutant TP53. Oncogene 37, 2793–2805 (2018). https://doi.org/10.1038/s41388-018-0130-6

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