<i>TMPRSS2-ERG</i> Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in <i>PTEN</i> and <i>TP53</i>-Mutated Prostate Cancer.

Abstract

<b>Purpose:</b> Deletions or mutations in <i>PTEN</i> and <i>TP53</i> tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor <i>ERG</i> is observed in approximately 50% of all prostate cancers, many of which also harbor <i>PTEN</i> and <i>TP53</i> alterations. However, the role of ERG in lineage plasticity of <i>PTEN</i>/<i>TP53</i>-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance.<b>Experimental Design:</b> We generated a <i>Pten</i>-negative/<i>Trp53</i>-mutated/<i>ERG</i>-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of <i>Pten</i>/<i>Trp53</i> alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray.<b>Results:</b> Transgenic <i>ERG</i> expression in mice blocked <i>Pten</i>/<i>Trp53</i> alteration-induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle-related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth.<b>Conclusions:</b> Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in <i>PTEN</i>/<i>TP53</i>-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of <i>PTEN</i>/<i>TP53</i>-altered, <i>RB1</i>-intact prostate cancer. <i>Clin Cancer Res; 24(18); 4551-65. ©2018 AACR</i>.