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.

中文翻译：

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用 CXCR2 阻断靶向细胞异质性治疗难治性前列腺癌。

针对雄激素受体 (AR) 的激素疗法最初对治疗前列腺癌 (PCa) 有效，但最终失败了。据推测，由 AR+ 管腔肿瘤细胞和 AR- 神经内分泌 (NE) 肿瘤细胞组成的 PCa 细胞异质性可能导致治疗失败。在这里，我们描述了基于细胞表面受体 CXC 基序趋化因子受体 2 (CXCR2) 从原发性新鲜人前列腺腺癌中成功纯化 NE 细胞。功能研究表明 CXCR2 是 NE 表型的驱动因素，包括 AR 表达缺失、谱系可塑性和对激素治疗的抗性。CXCR2 驱动的 NE 细胞通过为 AR+ 管腔细胞提供生存环境而对肿瘤微环境至关重要。我们证明 CXCR2 抑制和 AR 靶向的组合是小鼠异种移植模型中的有效治疗策略。这种策略有可能克服由肿瘤细胞异质性引起的治疗耐药性。