Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

作者：Ahmed A. Mohamed, Shyh‐Han Tan, Charles P. Xavier, Shilpa Katta, Wei Huang, Lakshmi Ravindranath, Muhammad Ameen Jamal, Hua Li, Meera Srivastava, Eri S. Srivatsan, Taduru Sreenath, David G. McLeod, Alagarsamy Srinivasan, György Petrovics, Albert Dobi, Shiv Srivastava · 发表于：Molecular Cancer Research · 年份：2017 · DOI：10.1158/1541-7786.mcr-17-0058 · 被引用次数：38 · 研究领域：Prostate Cancer Treatment and Research、Estrogen and related hormone effects、Cancer, Lipids, and Metabolism

Abstract The oncogenic activation of the ETS-related gene (ERG) due to gene fusions is present in over half of prostate cancers in Western countries. Because of its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for prostate cancer. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified, confirming that NOTCH factors are direct transcriptional targets of ERG. Inhibition of ERG in TMPRSS2-ERG–positive VCaP cells led to decreased levels of NOTCH1 and 2 proteins and downstream transcriptional targets and partially recapitulated the phenotypes associated with ERG inhibition. Regulation of NOTCH1 and 2 genes by ERG were also noted with ectopic ERG expression in LNCaP (ERG-negative prostate cancer) and RWPE-1 (benign prostate–derived immortalized) cells. Furthermore, inhibition of NOTCH by the small-molecule γ-secretase inhibitor 1, GSI-1, conferred an increased sensitivity to androgen receptor (AR) inhibitors (bicalutamide and enzalutamide) or the androgen biosynthesis inhibitor (abiraterone) in VCaP cells. Combined treatment with bicalutamide and GSI-1 showed strongest inhibition of AR, ERG, NOTCH1, NOTCH2, and PSA protein levels along with decreased cell growth, cell survival, and enhanced apoptosis. Intriguingly, this effect was not observed in ERG-negative prostate cancer cells or immortalized...