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

Abstract

The oncogenic activation of the ETS related gene (ERG) due to gene fusions is present in over half of prostate cancer (CaP) in Western countries. Due to its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for CaP. 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 NOTCH-1 and -2 proteins and downstream transcriptional targets and partially recapitulated the phenotypes associated with ERG inhibition. Regulation of NOTCH-1 and -2 genes by ERG were also noted with ectopic ERG expression in LNCaP (ERG-negative CaP) and RWPE-1 (benign prostate derived immortalized) cells. Furthermore, inhibition of NOTCH by the small molecule gamma-Secretase inhibitor 1, GSI-1, conferred an increased sensitivity to androgen receptor (AR) inhibitors (Bicalutamide, 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 benign/normal prostate epithelial cells. These data underscore the synergy of AR and NOTCH inhibitors in reducing the growth of ERG-positive CaP cells. Implications Combinational targeting of NOTCH and AR signaling has therapeutic potential in advanced ERG-driven prostate cancers.

TERF1 downregulation promotes the migration and invasion of the PC3 prostate cancer cell line as a target of miR‑155

“…In addition, it was also suggested that HIF-1α may be a potential molecular target of PCa (43). The Notch signaling pathway was discovered to serve an important role in the PCa cell proliferation and apoptosis (44). Nevertheless, there are few studies focusing on the role of the Notch signaling pathway on the invasion and metastasis of PCa.…”

Loss of Notch1 Activity Inhibits Prostate Cancer Growth and Metastasis and Sensitizes Prostate Cancer Cells to Antiandrogen Therapies

“…Work by Mohamed and colleagues found GSI can synergize with enzalutamide, abiraterone, as well as another antiandrogen, bicalutamide to decrease cell proliferation, viability, and apoptosis of ERG-positive prostate cancer cells (VCaP), as Notch1 and 2 were found to be targets of ERG (39). ERG is an ETS family transcription factor commonly found increased in prostate cancer in roughly 50% of patients due to gene fusions with TMPRSS2 serine protease (40).…”

Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth

“…The emerging strategies to inhibit ERG include direct as well as indirect targeting of ERG (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The ERG-targeted therapies include inhibition of the DNAbinding and transcription activator function of ERG, destabilization of ERG protein, inhibition of CaP-associated ERG mRNA, blocking direct ERG interacting co-activators or the simultaneous disruption of cooperating ERG upstream and downstream factors or its downstream signaling events, including NF-κB or NOTCH (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) April 30, 2018; DOI: 10.1158/0008-5472. CAN-17-2949 Taken together, ERG oncoprotein and the ERG network represent promising, however challenging targets for ERG positive CaP and other cancers.…”