Zenith Capital Corp. announced the publication of an important study which has uncovered the role of ZEN-3694, a BET bromodomain inhibitor (BETi), in overcoming the resistance of metastatic castration resistant prostate cancer (mCRPC) to androgen receptor signaling inhibitors (ARSi). The study, led by a team of renowned prostate cancer researchers, has been published in Clinical Cancer Research, a high impact journal. The study demonstrated that mCRPC, when treated with ARSi, can switch its lineage from adenocarcinoma to a more aggressive neuroendocrine type which is less dependent on androgen receptor signaling. This treatment induced neuroendocrine prostate cancer is becoming more prevalent with increasing use of ARSis and is associated with very poor patient clinical outcomes. ZEN-3694 inhibits BRD4 and E2F1 which epigenetically regulate this lineage switch. Blocking BET bromodomain proteins in cell models stopped the activation of this program that drives the development of neuroendocrine prostate tumors, the research team found. Furthermore, this was supported by clinical data from ZEN-3694 Phase 1b/2a mCRPC study which showed that ZEN-3694 was most effective in patients whose tumors were less dependent on androgen receptor signaling and did not respond to prior ARSi. High expression of BRD4 and E2F1 were also observed in the tumors of two patients with treatment emergent neuroendocrine prostate cancer, and both patients had a response to ZEN-3694 + enzalutamide, consistent with the role of ZEN-3694 in overcoming resistance to ARSi in this aggressive form of prostate cancer.