A novel method for reducing androgen receptor signalling in castration-resistant prostate cancer (CRPC) has been reported in Nature. Arul Chinnaiyan and colleagues at the University of Michigan used JQ1, a small-molecule inhibitor of the chromatin-binding protein BRD4, to disrupt transcriptional regulation downstream of androgen binding and receptor activation.

Proliferation of prostate cancer is initially dependent on androgens, and can be slowed by blocking androgen production or interaction with the androgen receptor. However, the effectiveness of androgen-deprivation therapy inevitably decreases as alternative mechanisms for androgen receptor signalling emerge, such as receptor amplification, mutation and alternative splicing, and activation of oncogenes, leading to the development of CRPC.

JQ1 inhibited proliferation ... inducing cell-cycle arrest and apoptosis

Ligand binding to the androgen receptor promotes nuclear translocation and transcriptional regulation of target genes. Chinnaiyan and his team identified an interaction between the N-terminal domain of the androgen receptor and the bromodomain-containing protein BRD4, which binds to acetylated chromatin and recruits transcriptional elongation factors and RNA polymerase II to gene promoters. This interaction was disrupted by JQ1, which binds to the bromodomain of BRD4. Furthermore, JQ1 inhibited proliferation of androgen-sensitive prostate cancer cell lines (but not of nonmalignant cells, nor of androgen-insensitive prostate cancer cell lines), inducing cell-cycle arrest and apoptosis. JQ1 induced global gene expression changes, with repression of genes activated by androgen receptor signalling, including KLK3 (PSA) and ERG.

Androgen receptor and BRD4 each have thousands of binding sites throughout the genome, and at 2,031 genetic loci the two proteins were found to be co-recruited. JQ1 reduced the binding of both proteins to these loci, resulting in more efficient repression of androgen receptor signalling than was seen with enzalutamide, which blocks ligand binding to the androgen receptor, preventing nuclear translocation.

JQ1 was also assessed in a mouse xenograft model of prostate cancer, where it led to a significant reduction in tumour volume and weight. Enzalutamide was less effective. JQ1 was well tolerated by the mice. This research raises the possibility that bromodomain inhibitors like JQ1, by acting downstream of androgen receptor activation, could provide a novel treatment pathway for prostate cancer.