Past, Current, and Future Strategies to Target ERG Fusion-Positive Prostate Cancer

SIMPLE SUMMARY: In addition to its role in development and in the vascular and hematopoietic systems, ERG plays a central role in prostate cancer. Approximately 40–50% of prostate cancer cases are characterized by ERG gene fusions, which lead to ERG overexpression. Importantly, inhibition of ERG activity in prostate cancer cells decreases their viability. Therefore, inhibiting ERG might represent an important step to improve treatment efficacy for patients with ERG-positive prostate tumors. Here, we summarize the attempts made over the past years to repress ERG activity, the current use of ERG fusion detection and the strategies that might be utilized in the future to treat ERG fusion-positive tumors. ABSTRACT: The ETS family member ERG is a transcription factor with physiological roles during development and in the vascular and hematopoietic systems. ERG oncogenic activity characterizes several malignancies, including Ewing’s sarcoma, leukemia and prostate cancer (PCa). In PCa, ERG rearrangements with androgen-regulated genes—mostly TMPRSS2—characterize a large subset of patients across disease progression and result in androgen receptor (AR)-mediated overexpression of ERG in the prostate cells. Importantly, PCa cells overexpressing ERG are dependent on ERG activity for survival, further highlighting its therapeutic potential. Here, we review the current understanding of the role of ERG and its partners in PCa. We discuss the strategies developed in recent years to inhibit ERG activity, the current therapeutic utility of ERG fusion detection in PCa patients, and the possible future approaches to target ERG fusion-positive tumors.