Targeting Poly(ADP-Ribose) Polymerase and the c-Myb–Regulated DNA Damage Response Pathway in Castration-Resistant Prostate Cancer

Abstract

Androgen deprivation is the standard systemic treatment for advanced prostate cancer (PCa), but most patients ultimately develop castration-resistance. We show here that MYB is transcriptionally activated by androgen deprivation or impairment of androgen receptor (AR) signaling. MYB gene silencing significantly inhibited PCa growth in vitro and in vivo. Microarray data revealed that c-Myb shares a substantial subset of DNA damage response (DDR) target genes with AR, suggesting that c-Myb may replace AR for the dominant role in the regulation of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures comprising AR, MYB, and their common DDR target genes are significantly correlated with metastasis, castration-resistance, recurrence, and shorter overall survival in PCa patients. We demonstrated in vitro that silencing of MYB, BRCA1 or TOPBP1 synergized with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) to increase cytotoxicity to PCa cells. We further demonstrated that targeting the c-Myb-TopBP1-ATR-Chk1 pathway by using the Chk1 inhibitor AZD7762 synergizes with OLA to increase PCa cytotoxicity. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the c-Myb-TopBP1-ATR-Chk1 pathway.

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“…Li et al recently found that ENZ increased expression of the proto-oncogene c-MYB, a transcription factor that has been shown to be upregulated in multiple malignancies [7]. The results of this study showed that c-Myb increases growth and metastatic potential of both AR-positive and AR-negative PCa cells [7].…”

“…The results of this study showed that c-Myb increases growth and metastatic potential of both AR-positive and AR-negative PCa cells [7]. c-Myb expression was increased in AR-positive, androgenindependent PCa cells compared with PCa cells that were dependent on androgens for growth.…”

“…On the basis of these results, the authors devised a combination therapeutic strategy with an inhibitor of c-Myb-Topbp1-ATR-Chk1 signaling, i.e., the Chk1 inhibitor AZD7762, and an inhibitor of poly(ADPribose) polymerase (PARP), i.e., olaparib. Results of in vitro and in vivo studies showed that this combination has synergistic effects in PCa models [7]. Thus, this study identified a gene signature which is co-regulated by AR and c-Myb, and which specifies a therapeutically actionable pathway for CRPC.…”

“…c-Myb expression was increased in AR-positive, androgenindependent PCa cells compared with PCa cells that were dependent on androgens for growth. Importantly, the results of this study showed that AR and c-Myb share a common set of target genes that include a DNA damage response signature that is strongly associated with cancer recurrence, castration resistance, and metastatic disease [7]. These results point to a mechanistic model in which ENZ-mediated derepression of c-Myb expression compensates for loss of AR activity by ENZ treatment through regulation of their common DNA damage response gene targets, which, in turn, mediates resistance to ENZ.…”

“…These results point to a mechanistic model in which ENZ-mediated derepression of c-Myb expression compensates for loss of AR activity by ENZ treatment through regulation of their common DNA damage response gene targets, which, in turn, mediates resistance to ENZ. Further experiments revealed that c-Myb regulates DNA damage response through Topbp1, the ataxia-telangiectasia and Rad3-related protein (ATR), and Chk1 protein, which regulate DNA damage response checkpoints [7]. On the basis of these results, the authors devised a combination therapeutic strategy with an inhibitor of c-Myb-Topbp1-ATR-Chk1 signaling, i.e., the Chk1 inhibitor AZD7762, and an inhibitor of poly(ADPribose) polymerase (PARP), i.e., olaparib.…”