Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy (ADT) regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and pre-clinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyper-physiological 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 (MDR) transporter ABCB1. SLC35F2 expression was significantly correlated with intra-tumor androgen levels in four distinct patient-derived xenografts (PDX) 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. Implications: The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155.
- Received September 22, 2016.
- Revision received December 3, 2016.
- Accepted December 22, 2016.
- Copyright ©2017, American Association for Cancer Research.