Abstract
ERG inhibitory peptides promote ERG degradation and suppress the growth of TMPRSS2–ERG+ tumors.
Major finding: ERG inhibitory peptides promote ERG degradation and suppress the growth of TMPRSS2–ERG+ tumors.
Mechanism: ERG inhibitory peptides block protein–protein interactions and disrupt ERG chromatin binding.
Impact: Inhibitory peptides may allow therapeutic targeting of ERG and other oncogenic transcription factors.
Gene rearrangements create fusion genes that drive the majority of prostate cancers. In approximately half of cases, the promoter of the androgen-responsive gene TMPRSS2 is fused to the coding region of the gene encoding the ERG transcription factor, resulting in overexpression of truncated ERG. Thus, ERG is an attractive therapeutic target, but transcription factors are widely considered to be undruggable. Wang and colleagues performed iterative screening of a phage display random peptide library to identify inhibitory small molecules, termed peptidomimetics, that target ERG. A total of 12 unique ERG-specific ERG-inhibitory peptides (EIP) were identified. The EIPs bound to the ETS DNA-binding domain of ERG and disrupted its interactions with DNA and other proteins. Synthetic peptides were generated and conjugated to a cationic motif to promote cellular uptake, and in a panel of prostate cancer cell lines, EIPs suppressed ERG-mediated cellular invasion. To allow for in vivo investigation, retroinverso EIPs (RI-EIP) were generated in which the L-amino acids were replaced with D-amino acids in a reversed sequence to promote resistance to proteolysis. RI-EIPs disrupted ERG protein–protein interactions and also destabilized ERG, resulting in enhanced proteasomal degradation. Further, RI-EIPs blocked the binding of ERG to chromatin, thereby inhibiting ERG-mediated transcription of target genes. RI-EIPs bound preferentially to the fusion transcript–derived ERG over wild-type ERG, and thus did not disrupt ERG-mediated angiogenesis. In prostate cancer xenografts expressing TMPRSS2–ERG, RI-EIPs promoted ERG degradation and suppressed tumor growth and lung metastasis, but had no effect on the growth of tumors lacking fusions involving ERG or the related ETV1 gene. Collectively, these findings suggest that EIPs warrant further investigation for the treatment of TMPRSS2–ERG-positive prostate cancer, and suggest the possibility of developing peptidomimetics for therapeutic targeting of oncogenic transcription factors in a wide variety of tumor types.
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