Targeting Androgen-Independent Prostate Cancer with BET Inhibitors INCB054329 and INCB057643: A Promising Therapeutic Approach

Prostate cancer remains a significant contributor to cancer-related mortality globally. The role of transcriptional factors and epigenetic regulators in the advancement and resistance to treatment of prostate cancer has been identified, highlighting potential targets for novel therapeutic approaches. BET proteins, functioning as transcriptional co-activators, are involved in the interaction with various regulatory molecules at gene promoters and enhancers. The disruption of transcriptional regulatory complexes by BET inhibitors (BETi) has been shown to have a wide range of anticancer effects.

Two such BETi, INCB054329 and INCB057643, have demonstrated pre-clinical efficacy against both hematological and solid tumors and are currently undergoing clinical evaluation in patients with advanced cancer. This study marks the first exploration of their efficacy in prostate cancer, examining their impact on androgen-dependent and independent models through in vitro and in vivo methods.

The study evaluated the influence of these compounds on cell proliferation, colony formation, and tumor-sphere formation in various cell lines, including androgen-dependent (LNCaP and VCaP) and androgen-independent (DU145, PC3, 22Rv1) types. The in vivo assessment involved testing the drugs' antitumor potential in mice with subcutaneously implanted 22Rv1 xenografts, administered orally for a period of three weeks.

Both compounds were found to inhibit the proliferation of prostate cancer cell lines, with a more pronounced effect on androgen-dependent cells in short-term assays. However, all cell lines exhibited heightened sensitivity to the BETi in colony and tumor-sphere formation assays, with the androgen-independent 22Rv1 cells showing a particularly strong response. The in vivo treatment with INCB054329 and INCB057643 resulted in a significant reduction in tumor growth and weight in the mice.

The findings suggest that despite a preferential effect on androgen-sensitive cells in short-term assays, both compounds also show considerable activity against an androgen-independent model, indicating their potential as a therapeutic option for castration-resistant prostate cancer.

Reference: Ramiro Vázquez et al. "BET inhibitors INCB054329 and INCB057643 display significant activity in androgen-independent prostate cancer models" In Proceedings of the American Association for Cancer Research Annual Meeting 2017; Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5080. doi:10.1158/1538-7445.AM2017-5080.