Despite the wide characterization of the transcription factors associated with cancers, few therapies have been developed to target these “undruggable targets” because of their characteristic lack of active sites. The TMPRSS2-ERG translocation is an attractive candidate for therapeutic intervention because the translocation of the androgen-sensitive regulatory element of TMPRSS2 upstream of the ETS-family transcription factor ERG results in the over-expression of the TMPRSS2-ERG fusion product, leading to increased proliferation, invasion, and survival of prostate tumor cells.
Our research investigated a number of drugs targeting several dozen kinases, identified by a high-throughput shRNA knockdown screen, whose mRNA expression signatures upon knockdown matched ERG knockdown mRNA expression signatures. If an identified kinase plays an essential role in TMPRSS2-ERG prostate cancer development, then its drug-induced inhibition will manifest itself in cancer cell viability and expression at the transcriptional and/or translational level.
ERG-expressing prostate cancer cells (VCaP) were treated with various kinase inhibitor drugs. Cells treated with mTOR inhibitors showed reduced ERG protein expression and increased ERG mRNA expression by western blot and qPCR, suggesting mTOR involvement in post-translational ERG modification and a negative feedback loop regulating ERG protein levels. The role mTOR plays in regulating ERG may be further confirmed by phenotypic changes such as reduced invasion to further elucidate the role of kinase inhibition on other elements of the ERG pathway. Positive results may lead to potential therapies for TMPRSS2-ERG-induced prostate cancer and, moreover, shed light on the little-understood ERG signaling pathway.
PROJECT: Inhibition of ERG Pathway Kinases Reveals Potential Prostate Cancer Therapeutics
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