Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer

Abstract

Cellular heterogeneity of PCa contributes to hormonal therapy failure, but CXCR2 on neuroendocrine cells is a potential therapeutic target. Finding tumor cells and killing them too Treatments targeting the androgen receptor, a mainstay of prostate cancer therapy, do not usually cure the disease and eventually lose their effectiveness. A major cause of this therapeutic resistance is the presence of neuroendocrine tumor cells, which are not sensitive to androgen inhibition. Li et al. determined that neuroendocrine prostate cancer cells express a chemokine receptor called CXCR2 and showed that it can be used to help identify these cells in tumors and also plays a functional role in their resistance to treatment, making it a viable therapeutic target. Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR− neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.