Inhibition of ERG-Pathway Kinases Reveals Potential Prostate Cancer Theraputics

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.  A translocation of the androgen-sensitive regulatory element of TMPRSS2 upstream of the ETS-family transcription factor ERG results in the overexpression of the TMPRSS2-ERG fusion product, leading to increased proliferation, invasion, and survival of prostate tumor cells, making the TMPRSS2-ERG translocation an attractive candidate for therapeutic intervention. 

A high-throughput shRNA knockdown screen identified several dozen kinases whose mRNA expression signatures upon knockdown matched ERG knockdown mRNA expression signatures. If any of the identified kinases 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.  

Media treatment of ERG-expressing prostate cancer cells (VCaP) with varying concentrations of mTOR, MAPK, and ACVR1B inhibitor drugs resulted in morphological change and moderate to complete cell toxicity.  Western blot protein expression data suggest that there may be an effect on ERG protein levels present in the cell, but whether these changes reflect reduced expression or modified stability remains yet to be investigated.  We plan to measure ERG mRNA expression, expression of downstream targets of ERG, and 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.