In addition, CBP and p300 mRNA expression significantly (all P ≤ 0.001) associated with AR mRNA expression (Supplementary Fig. Analysis of mRNA sequencing data from 550 primary prostate cancer samples and 120 mCRPC samples demonstrated that CBP and p300 mRNA expression significantly (all P ≤ 0.001) associated with the AR signature in primary prostate cancer and mCRPC ( Fig. The AR signature was determined using two previously described gene-expression signatures (Supplementary Table S1 refs. Taken together, targeting p300/CBP is an attractive therapeutic strategy to abrogate persistent AR signaling in advanced prostate cancer.īecause CBP and p300 are known coactivators of the AR, which enhance AR activity, we determined the association of CBP and p300 mRNA expression with an AR signature in primary prostate cancer and metastatic castration-resistant prostate cancer (mCRPC refs. Importantly, they have been described as potent coactivators of the AR, and perturbation of p300/CBP function in prostate cancer models has been reported to decrease AR function and reduce tumor cell growth ( 25, 28–38). These domains interact with a plethora of transcription factors, as well as the general transcriptional machinery, and therefore regulate multiple cellular processes ( 27). Their functional activity is, at least in part, mediated by two conserved regions: a catalytic histone acetyltransferase domain and a bromodomain. p300 and CBP are paralogous, highly conserved proteins that serve as transcriptional regulators. The development and progression of CRPC is characterized by continued AR signaling through either overexpression of the AR, mutations of the AR ligand-binding domain, tumor-derived androgen production, expression of constitutively active AR splice variants (AR-SV) of which AR-V7 remains the best studied, or increased expression of AR coregulators including the transcription factor coactivator proteins p300/CBP ( 9–26). Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. In AR-SV–driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC–regulated gene expression. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV).
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