ERG function in prostate cells is regulated by distinct positive feedback loops depending on AKT signaling status.

A chromosomal rearrangement that causes aberrant expression of the ERG transcription factor is the most common genomic alteration in prostate cancer. Expression of ERG in prostate cells can promote either luminal epithelial or mesenchymal cell fates depending on the status of the PI3K/AKT signaling pathway. Phosphorylation of ERG by ERK is important for oncogenic activity and can be regulated by the TLR4 signaling pathway. Here we found that the PI3K/AKT pathway not only regulated how ERG promoted distinct cell types within prostate cells, but also altered the positive-feedback loops that drove ERG phosphorylation. Activation of AKT signaling switched the upstream pathway that promotes ERG phosphorylation from TLR4 to VEGF. Inhibition of the PI3K/AKT pathway in ERG-positive prostate cells resulted in loss of androgen receptor expression, gain of mesenchymal markers and loss of sensitivity to androgen receptor inhibition. Further, androgen depletion reduced PI3K/AKT activity while increasing MEK/ERK activity and relative ERG phosphorylation. In a xenograft model, single agent inhibition of TLR4 or VEGFA reduced ERG phosphorylation, tumor size, and luminal marker expression but increased mesenchymal marker expression. Combination TLR4/VEGFA inhibition reduced tumor size and reduced both luminal and mesenchymal markers. These findings suggest novel combinatorial treatments for ERG-positive prostate cancer.