Targeting CXCR2+ Neuroendocrine-like Cells for the Treatment of Castration-resistant Prostate Cancer
- Author(s): Li, Yanjing
- Advisor(s): Wu, Lily
- et al.
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy in men and the second leading cause of cancer-related deaths in the US. Men with PCa that has recurred after surgery or radiation therapy usually respond to androgen deprivation therapy (ADT); however despite initial responses rate of 80 to 90 percent, nearly all men eventually develop progressive disease following ADT; this is referred to as castration-resistant prostate cancer (CRPC), which remains an incurable disease. It has been reported that neuroendocrine (NE) cell type in prostate cancer is highly associated with castration-resistant disease. However, the exact role of NE cells in promoting the transition from castration-sensitive cancer to castration-resistant disease is not fully understood. The goal of this study was to investigate the gene expression profile, cellular function and therapeutic resistant properties of NE cells purified through CXCR2 surface marker from prostate adenocarcinoma. We further investigated the role of CXCR2 in mediating CRPC carcinogenesis and explore the use of CXCR2 inhibitor combine with Enzalutamide as a potential therapy for advanced prostate cancer. In this research, we have identified a novel cross-talk between neuroendocrine cells in hormone naï¿½ve prostate cancer with both prostate cancer progression and hormonal therapy resistance. We have demonstrated that C-X-C motif chemokine receptor 2 (CXCR2) is a unique surface marker of neuroendocrine cells in prostate cancer and it is over-expressed in metastatic castration resistant, high grade, and NEPC patient cases. Importantly, we discovered that CXCR2 plays a critical role in facilitating this intercellular communication and NEPC transformation from typical prostate adenocarcinoma. CXCR2 overexpression led to enzalutamide resistance, loss of AR expression, and lineage plasticity with acquisition of stem cell-like properties. We further demonstrated that CXCR2 inhibition can prevent/delay enzalutamide resistance and restore AR function, leading to reductions in tumor burden. This research provides the mechanism for the first time of therapeutic resistance mediated by NE cells and raises the possibility to the final cure of lethal prostate cancer through CXCR2 blocker.