Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

  title={Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer},
  author={Ling Li and Lisa Hobson and Laura Perry and Bethany Clark and Susan Heavey and Aiman Haider and Ashwin Narasimha Sridhar and Greg Shaw and John Kelly and Alex Freeman and Ian D Wilson and Hayley C. Whitaker and Elmar Nurmemmedov and Sebastian Oltean and Sean R Porazinski and Michael Ladomery},
  journal={British Journal of Cancer},
  pages={1024 - 1032}
The ERG oncogene, a member of the ETS family of transcription factor encoding genes, is a genetic driver of prostate cancer. It is activated through a fusion with the androgen-responsive TMPRSS2 promoter in 50% of cases. There is therefore significant interest in developing novel therapeutic agents that target ERG. We have taken an antisense approach and designed morpholino-based oligonucleotides that target ERG by inducing skipping of its constitutive exon 4. We designed antisense morpholino… 
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TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation
Evaluation of the transcriptome and specific gene promoters in ERG siRNA-treated cells and investigation of gene expression signatures of human prostate tumors revealed ERG-mediated activation of C-MYC oncogene and the repression of prostate epithelial differentiation genes (PSA and SLC45A3/Prostein).
The Evolutionarily Conserved Cassette Exon 7b Drives ERG's Oncogenic Properties
Findings show that the evolutionarily conserved cassette exon 7b is central to ERG's oncogenic properties and is required for the induction of tissue nonspecific alkaline phosphatase.
YK-4-279 Inhibits ERG and ETV1 Mediated Prostate Cancer Cell Invasion
YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion, which may have an impact on metastasis in prostate cancer.
TMPRSS2‐ERG Fusion Promotes Recruitment of Regulatory T cells and Tumor Growth in Prostate Cancer
Fluorescence in situ hybridization analysis showed that the TMPRSS2‐ERG fusion gene was positive in prostate cancer and that the messenger RNA and protein expression of ERG were significantly up‐regulated in prostatecancer biopsy tissues.
Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts.
The results indicate that TMPRSS2/ERG fusion isoforms have variable biological activities promoting tumor initiation and progression and are consistent with previous clinical observations indicating that certain TMPR SS2-ERG fusionisoforms are significantly correlated with more aggressive disease.
Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG‐positive prostate cancer
The hypothesis that HDACi, especially in combination with androgen deprivation, is effective against TMPRSS2‐ERG‐fusion positive prostate cancer in vitro is supported and therapeutic paradigms to be tested in vivo are suggested.
Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer.
The mechanisms by which ETS fusions mediate their effects are investigated, and it is found that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs).
ERG is a critical regulator of Wnt/LEF1 signaling in prostate cancer.
This study provides an important mechanism of activation of Wnt signaling in prostate cancer and nominates LEF1 as a critical mediator of ERG-induced tumorigenesis and Wnt/LEF1 pathway might provide novel targets for therapeutic management of patients with fusion-positive prostate cancer.
Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex 2, allowing target gene activation
Findings have identified critical molecular mechanisms involving ERK-mediated ERG activation that could be exploited for therapeutic intervention in ERG-positive prostate cancers.
The oncogene ERG: a key factor in prostate cancer
ERG’s structure and function is reviewed, and its role in prostate cancer is discussed, and potential new therapies that are based on targeting ERG are discussed.