Novel Mechanisms of Resistance to Enzalutamide in Prostate Cancer

Abstract

Prostate cancer (PCa) is the second most common invasive cancer in men worldwide. In Ireland, PCa is the third leading cause of male cancer related mortality. AR directed therapies have remained the primary therapeutic strategy for individuals with PCa as this disease is principally driven by androgens acting through the AR. Recent advances in anti-androgen therapy have resulted in the introduction of novel powerful AR inhibitors like enzalutamide, which have shown superior efficacy than first generation anti-androgen therapies. Despite its initial effectiveness, primary or acquired resistance remains a significant clinical issue. Ongoing translational methods are being employed to further understand the molecular mechanisms of enzalutamide resistance PCa. The data produced in this project characterised circRNA profiles in PCa and demonstrated for the first time that overexpression of certain circRNA enhanced resistance to enzalutamide in vitro. This study examined a variety of methodologies to assess circRNA expression in PCa, and has laid the groundwork for future research in this novel area. This study also used RNA-Seq to identify a number of pathways that may provide more insight into the molecular mechanisms of enzalutamide resistance in PCa. Although molecular profiling is not, yet the clinical standard of care in PCa, increasing evidence is emerging to support its utility in guiding therapeutic decisions. This project included a retrospective study to evaluate the landscape of actionable gene mutations in Irish men with metastatic castrate resistant PCa through next generation sequencing. There was a high rate of potentially actionable gene mutations identified, which could have therapeutic implications in the future. Notably, between 13% and 25% of participants in this research had somatic mutations in the DNA damage response and repair (DDR) gene which can be targeted with a PARP Inhibitor.