Functional Interplay Between PARP, AR and DNA Damage

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

Project Summary Men carrying germline mutations in DNA damage response (DDR) genes including most notably BRCA2 and BRCA1 have a very substantially increased lifetime risk of developing prostate cancer. BRCA1 and BRCA2 mutation carriers develop prostate cancer at a younger age and present with more aggressive disease. These men are at higher risk of recurrence and prostate cancer death. Somatic loss of BRCA1 or BRCA2 also occurs in a subset of prostate cancers and is also associated with poor outcomes. Tumors lacking BRCA1 or BRCA2 are sensitive to inhibitors of poly (ADP-ribose) polymerase (PARP). PARP inhibitors have been approved for the treatment of men with metastatic castration-resistant prostate cancer (CRPC) and are being tested in hormone- sensitive metastatic disease. There is continued uncertainty concerning the mechanism underlying the efficacy of PARP inhibitors in tumors harboring defects in DDR genes involved in homologous recombination (HR) mediated repair and whether PARP inhibitors have activity in HR-proficient prostate as well. The role of "PARP trapping" on chromatin as critical to the therapeutic efficacy of PARP inhibitors is supported by studies demonstrating that the loss of PARP1 can be a mechanism of resistance to PARP inhibitors. Alternatively, a role for PARP activity in multiple DNA repair pathways may lead to a synthetic lethality in tumors harboring HR defects. Whether this is also the case in HR-proficient tumors and whether AR antagonism can increase the sensitivity to PARP inhibition remains unclear. Several members of the family of PARP enzymes including PARP1 and PARP2 have been shown to play important roles distinct from DDR, however, including the regulation of chromatin structure and transcription. In addition, PARP1 and PARP2 have been implicated in various aspects of androgen receptor (AR) regulated gene expression. The impact of PARP inhibition on the AR cistrome and AR regulated gene expression during prostate cancer progression has yet to be fully elucidated. Also, whether PARP1-selective inhibitors currently in clinical development might alter the balance between the various functions of PARP impacting the effectiveness of PARP inhibition in CRPC remains to be determined. In addition to a role for PARP in the AR transcriptional program, DNA damage has been shown to be both the result of AR action and to alter AR signaling. Whether DNA damage resulting from the loss of BRCA1 or BRCA2 alters AR function or whether BRCA1 or BRCA2 play direct roles in AR function remains to be defined. Thus a detailed understanding of the functional interplay between AR, PARP, BRCA1 and 2, and DNA damage will inform patient selection for treatment with AR-pathway targeted therapies including androgen synthesis inhibitors, direct AR antagonists and AR agonists such as supraphysiological testosterone (SPT) and PARP inhibitors in both CRPC and hormone sensitive prostate cancer.