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

Abstract

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.

Scarless Enriched selection of Genome edited Human Pluripotent Stem Cells Using Induced Drug Resistance

“…SLC35F2 , a membrane solute carrier, was the transcript most correlated with YM155 sensitivity (Fig. 1B, left panel), suggesting that cellular import of YM155 by SLC35F2 is responsible for the highly selective cytotoxicity of the drug in hPSCs (Lee et al, 2013b); this is consistent with previous reports in cancer models (Nyquist et al, 2017; Radic-Sarikas et al, 2017; Winter et al, 2014). Using a database of gene expression profiles (http://nextbio.com) (Kupershmidt et al, 2010), we compared relative SLC35F2 expression between 24 human embryonic stem cells (hESCs) and various cancer cell lines; PC-3, a human prostate cancer cell line, was used as a positive control (P.C.)…”

The pathognomonic FOXL2 C134W mutation alters DNA binding specificity

“…Strikingly, all four genes identified are highly relevant to cancer biology ( Table 1). CHRNA9 has been previously identified as highly expressed in breast cancer 41 ; S1PR1 is a G-protein coupled receptor involved in the cytokine signaling in the immune system, and is known to be up-regulated in ovarian cancer tissues and cell lines 42 ; SLC35F2 is a potential oncogene highly expressed in non-small-cell lung carcinoma 43 , indispensable for papillary thyroid carcinoma progression 44 , and regulated by androgen receptor axis signaling in prostate cancer 45 ; ATP5E is known to be down regulated in papillary thyroid cancer 46 . These findings prompted us to examine whether those genes were also expressed in primary AGCTs 7 .…”

Solute carrier family 35 member F2 is indispensable for papillary thyroid carcinoma progression through activation of transforming growth factor‐β type I receptor/apoptosis signal‐regulating kinase 1/mitogen‐activated protein kinase signaling axis

“…Bu et al report that SLC35F2 was highly expressed in non‐small cell lung cancer (NSCLC) tissues, was associated with the pathological stage and had prognostic value in NSCLC . Nyquist et al found that SLC35F2 expression was linked to intratumor androgen levels and was regulated by the androgen receptor axis signaling in prostate cancer . Recently, a study verified SLC35F2 as a cargo of anti‐cancer drug YM155 and determined that lack of SLC35F2 was capable of conferring drug resistance .…”

“…11 Nyquist et al found that SLC35F2 expression was linked to intratumor androgen levels and was regulated by the androgen receptor axis signaling in prostate cancer. 12 Recently, a study verified SLC35F2 as a cargo of anti-cancer drug YM155 and determined that lack of SLC35F2 was capable of conferring drug resistance. 13 Therefore, SLC35F2 could be used as a clinical biomarker for YM155 susceptibility.…”