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DNA damage response and prostate cancer: defects, regulation and therapeutic implications

Oncogene volume 34, pages 2815–2822 (2015)Cite this article

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Abstract

DNA damage response (DDR) includes the activation of numerous cellular activities that prevent duplication of DNA lesions and maintain genomic integrity, which is critical for the survival of normal and cancer cells. Specific genes involved in the DDR such as BRCA1/2 and P53 are mutated during prostate cancer progression, while various oncogenic signaling such as Akt and c-Myc are activated, enhancing the replication stress and increasing the genomic instability of cancer cells. These events may render prostate cancer cells particularly sensitive to inhibition of specific DDR pathways, such as PARP in homologous recombination DNA repair and Chk1 in cell cycle checkpoint and DNA repair, creating opportunities for synthetic lethality or synergistic cytotoxicity. Recent reports highlight the critical role of androgen receptor (AR) as a regulator of DDR genes, providing a rationale for combining DNA-damaging agents or targeted DDR inhibitors with hormonal manipulation or AR inhibition as treatment for aggressive disease. The aims of this review are to discuss specific DDR defects in prostate cancer that occur during disease progression, to summarize recent advances in understanding the regulation of DDR in prostate cancer, and to present potential therapeutic opportunities through combinational targeting of the intact components of DDR signaling pathways.

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Acknowledgements

We thank Kathryn L Hale, MS, MLIS, for her expert editorial assistance. This research is supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant, 5 P30 CA016672.

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  1. S Karanika and T Karantanos: These authors contributed equally to this work.

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  1. Department of Genitourinary Medical Oncology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Karanika, T Karantanos, L Li, P G Corn & T C Thompson

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Karanika, S., Karantanos, T., Li, L. et al. DNA damage response and prostate cancer: defects, regulation and therapeutic implications. Oncogene 34, 2815–2822 (2015). https://doi.org/10.1038/onc.2014.238

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  • DOI: https://doi.org/10.1038/onc.2014.238

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