Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

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.
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. Mol Cancer Res; 15(5); 521–31. ©2017 AACR.

Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Nyquist, M. D., Corella, A., Burns, J., Coleman, I., Gao, S., Tharakan, R., Riggan, L., Cai, C., Corey, E., Nelson, P. S., Mostaghel, E. A. Tags: Cell Death and Survival Source Type: research