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Review
. 2015 May 28;34(22):2815-22.
doi: 10.1038/onc.2014.238. Epub 2014 Aug 18.

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

S Karanika  1 , T Karantanos  1 , L Li  1 , P G Corn  1 , T C Thompson  1
Affiliations
Review

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

S Karanika et al. Oncogene. .

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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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. DDR defects implicated in initiation and progression of prostate cancer and opportunities for synthetic lethality
Replication stress, irradiation (IR) and ultraviolet light (UV) promote DSBs and SSBs, respectively, leading to activation of multiple pathways regulating DNA repair, including ATM/Chk2/p53, ATR/Chk1 and PARP signaling. These events promote repair of the damage providing survival benefit to cancer cells under stimuli inducing genomic instability. During prostate cancer progression, genetic abnormalities such as polymorphisms and mutations or deletions of p53, ATM, Chk2 and BRCA1/2 (indicated by red bold slashes) have been reported, which make these pathways nonfunctional rendering other aspects of DDR critical for the cells’ survival. Inhibition of alternative signaling (i.e., Chk1 and PARP) with DDR-targeted agents (Chk1, ATR and PARP inhibitors) may provide opportunities for synthetic lethality in tumors with defective DDR. Clinically, the identification of particular defects in the DDR system may create opportunities for personalized treatment in patients with aggressive, hormonal resistant prostate cancer. BER: base excision repair; HR: homologous recombination.
Figure 2
Figure 2. Strategies for combination therapies in aggressive prostate cancers focusing on AR inhibition and androgen depletion
Androgen receptor (AR) regulates multiple aspects of DDR during prostate cancer development. DNA damage induced by DNA-damaging agents such as carboplatin and replication stress activate DDR, many aspects of which, such as ATM/Chk2 and NHEJ, are mediated by AR. Mutations and deletions of BRCA and ATM/Chk2 signaling (molecules represented by red ovals with yellow outline) render Chk1/ATR and PARP critical for prostate cancer cell survival. Inhibition of AR by androgen-depletion therapy (ADT) or enzalutamide (ENZA) is expected to render prostate cancer cells particularly sensitive to inhibition of PARP (PARPi) and AR-independent DDR signaling such as Chk1/ATR (Chk1i and ATRi) with targeted agents. Finally, combination of DNA-damaging agents such as carboplatin with inhibition of DDR may be a reasonable therapeutic approach for anaplastic (AR negative) disease. HR, homologous repair; NHEJ, nonhomologous end joining.
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