Nyquist Michael D, Corella Alexandra, Burns John, Coleman Ilsa, Gao Shuai, Tharakan Robin, Riggan Luke, Cai Changmeng, Corey Eva, Nelson Peter S, Mostaghel Elahe A
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Virginia Mason Medical Center, Seattle, Washington.
Mol Cancer Res. 2017 May;15(5):521-531. doi: 10.1158/1541-7786.MCR-16-0315-T.
Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and preclinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyperphysiologic levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and, therefore, may identify patients who are highly responsive to YM155 treatment.
The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155.
雄激素受体（AR）信号传导是前列腺癌的基础，也是转移性疾病的主要治疗靶点。然而，严格的雄激素剥夺治疗方案会降低生活质量，并且在降低死亡率方面基本未取得成功。最近的临床和临床前研究利用AR信号传导通过给予超生理水平的睾酮来引发生长抑制和分化作用的二分能力。在本研究中，高通量药物筛选确定了高雄激素治疗与YM155（一种生存素（BIRC5）的转录抑制剂）之间的强效协同作用。这种相互作用是由AR直接转录上调YM155转运体SLC35F2介导的。雄激素介导的YM155诱导的细胞死亡被多药耐药转运体ABCB1的过表达完全阻断。在四个不同的患者来源异种移植模型中，SLC35F2表达与肿瘤内雄激素水平显著相关，并且在去势抵抗性转移的大型基因表达数据集中与AR活性评分相关。一部分肿瘤的SLC35F2表达显著升高，因此，可能识别出对YM155治疗高度敏感的患者。
雄激素治疗与YM155联合代表一种新型药物协同作用，并且SLC35F2可能作为对YM155反应的临床生物标志物。
