Progression to castration-resistant prostate cancer after androgen ablation therapy is primarily due to deregulated androgen receptor signaling. Treatment with agents that target such signaling, such as abiraterone (Zytiga) and enzalutamide (Xtandi), has been successful. However, durable response is infrequently achieved, likely reflecting development of acquired resistance.
BRD4 is a member of the BET family of bromodomain-containing proteins that influence transcription by binding to acetylated histones. Recently, selective small-molecule inhibitors (JQ1 and I-BET762) that target the amino-terminal bromodomains of BRD4 have been found to exert antiproliferative effects in several cancers.
In a study reported in Nature, Asangani and colleagues showed that androgen receptor signaling–competent human castration-resistant prostate cancer cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. JQ1 was shown to inhibit the physical interaction of BRD4 with the N-terminal domain of the androgen receptor and, like enzalutamide, disrupt androgen receptor recruitment to target gene loci. Unlike enzalutamide, JQ1 was found to function downstream of the androgen receptor and to more effectively inhibit both BRD4 localization to receptor target loci and androgen receptor–mediated gene transcription, with effects including inhibition of TMPRSS2-ERG gene fusion and its oncogenic activity.
BET bromodomain inhibition was found to be more effective in reducing tumor growth than direct androgen receptor inhibition in castration-resistant prostate cancer xenograft mouse models.
The investigators concluded, “Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.” ■
Asangani IA, et al: Nature 510:278-282, 2014.