TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53 -Mutated Prostate Cancer

• Published in: Clinical cancer research 2018-09, Vol.24 (18), p.4551-4565
• Main Authors: Blee, Alexandra M, He, Yundong, Yang, Yinhui, Ye, Zhenqing, Yan, Yuqian, Pan, Yunqian, Ma, Tao, Dugdale, Joseph, Kuehn, Emily, Kohli, Manish, Jimenez, Rafael, Chen, Yu, Xu, Wanhai, Wang, Liguo, Huang, Haojie
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - pharmacology; Animals; Benzamides; Cell Lineage - drug effects; Cell Lineage - genetics; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 6 - genetics; Disease Models, Animal; Drug Resistance, Neoplasm - genetics; Epithelial Cells - drug effects; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Transgenic; Nitriles; Oncogene Proteins, Fusion - genetics; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; PTEN Phosphohydrolase - genetics; Serine Endopeptidases - genetics; Transcriptional Regulator ERG - genetics; Tumor Suppressor Protein p53 - genetics; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0653

Deletions or mutations in and tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor is observed in approximately 50% of all prostate cancers, many of which also harbor and alterations. However, the role of ERG in lineage plasticity of / -altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance. We generated a -negative/ -mutated/ -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 / 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. Transgenic expression in mice blocked / 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. Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in / -altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of / -altered, -intact prostate cancer. .