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

Clin Cancer Res. 2018 Sep 15;24(18):4551-4565. doi: 10.1158/1078-0432.CCR-18-0653. Epub 2018 May 29.


Purpose: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance.Experimental Design: We generated a Pten-negative/Trp53-mutated/ERG-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 Pten/Trp53 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.Results: Transgenic ERG expression in mice blocked Pten/Trp53 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.Conclusions: Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer. Clin Cancer Res; 24(18); 4551-65. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • PTEN Phosphohydrolase / genetics*
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Serine Endopeptidases / genetics*
  • Transcriptional Regulator ERG / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Xenograft Model Antitumor Assays


  • Androgen Antagonists
  • Benzamides
  • ERG protein, human
  • Nitriles
  • Oncogene Proteins, Fusion
  • Transcriptional Regulator ERG
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Phenylthiohydantoin
  • enzalutamide
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Serine Endopeptidases
  • TMPRSS2 protein, human