Abstract 5257: Activation of the oncogene ERG by the Ras/ERK and PI3K/AKT pathways

The TMPRSS2-ERG re-arrangement occurs in ~50% of prostate cancers and results in androgen driven aberrant expression of the transcription factor ERG. ERG acts as an oncogene in the prostate and activates a transcriptional program which results in cell migration, epithelial to mesenchymal transition, and tumorigenesis. Activation of both the Ras/ERK and PI3K/AKT signaling pathways has been demonstrated to be necessary for transcription of ERG target genes and is required for ERG mediated phenotypes in the prostate, however, the exact mechanism of this requirement is not known. Recently, our lab demonstrated that ERK1/2 phosphorylation of ERG abrogates ERG’s interaction with the co-repressor EZH2 and the PRC2 and is necessary for ERG-mediated transcription of genes involved in cell migration. It has been demonstrated that ERG also requires activation of the PI3K/AKT pathway for ERG-mediated tumorigenesis in the prostate, however how the Ras/ERK and PI3K/AKT pathways cooperate in transcription of ERG target genes and ERG mediated phenotypes is not well understood. Here we use genomic and transcriptomic approaches to demonstrate that Ras/ERK and PI3K/AKT pathway requirements for ERG function differ between distinct ERG-mediated mediated gene expression programs which correlate with distinct phenotypic outputs. Overall, our results demonstrate how the Ras/ERK and PI3K/AKT pathways contribute to ERG mediated tumorigenesis in the prostate and point the way towards new therapeutic targets. Citation Format: Brady G. Strittmatter, Peter Hollenhorst. Activation of the oncogene ERG by the Ras/ERK and PI3K/AKT pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5257.