Down-regulation of ADRB2 expression is associated with small cell neuroendocrine prostate cancer and adverse clinical outcomes in castration-resistant prostate cancer

Daniel H. Kwon, Li Zhang, David A. Quigley, Adam Foye, William S. Chen, Christopher K. Wong, Felix Y. Feng, Adina Bailey, Jiaoti Huang, Joshua M. Stuart, Verena Friedl, Alana S. Weinstein, Tomasz M. Beer, Joshi J. Alumkal, Matthew Rettig, Martin Gleave, Primo N. Lara, George V. Thomas, Patricia Li, Austin LuiEric J. Small, Rahul R. Aggarwal

Research output: Contribution to journalArticle

Abstract

Objectives: The net oncogenic effect of β2-adrenergic receptor ADRB2, whose downstream elements induce neuroendocrine differentiation and whose expression is regulated by EZH2, is unclear. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods and materials: This was a retrospective analysis of a multi-center, prospectively enrolled cohort of mCRPC patients. Metastatic biopsies were obtained at progression, and specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and clustering based on unsupervised hierarchical transcriptome analysis and correlated with EZH2 expression; an external dataset was used for validation. The association between ADRB2 expression and overall survival (OS) was assessed by log-rank test and a multivariable Cox proportional hazard model. Results: One hundred and twenty-seven patients with progressive mCRPC had sufficient metastatic tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P < 0.01) and correlated inversely with EZH2 expression (r = -0.28, P < 0.01). These findings were validated in an external cohort enriched for neuroendocrine differentiation. Patients with tumors harboring low ADRB2 expression (lowest quartile) had a shorter median OS than those with higher (9.5 vs. 20.5 months, P = 0.02). In multivariable analysis, low ADRB2 expression was associated with a trend toward shorter OS (HR for death = 1.54, 95%CI 0.98–2.44). Conversely, higher expression of upstream transcriptional regulator EZH2 was associated with shortened OS (HR for death = 3.01, 95%CI 1.12–8.09). Conclusions: Low ADRB2 expression is associated with neuroendocrine differentiation and is associated with shortened survival. EZH2 is a potential therapeutic target for preventing neuroendocrine transdifferentiation and improving outcomes in mCRPC. Further studies of agents targeting β-adrenergic signaling are warranted.

Original languageEnglish (US)
JournalUrologic Oncology: Seminars and Original Investigations
DOIs
StateAccepted/In press - 2020

Keywords

  • ADRB2
  • Beta adrenergic receptor
  • EZH2
  • Neuroendocrine
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

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    Kwon, D. H., Zhang, L., Quigley, D. A., Foye, A., Chen, W. S., Wong, C. K., Feng, F. Y., Bailey, A., Huang, J., Stuart, J. M., Friedl, V., Weinstein, A. S., Beer, T. M., Alumkal, J. J., Rettig, M., Gleave, M., Lara, P. N., Thomas, G. V., Li, P., ... Aggarwal, R. R. (Accepted/In press). Down-regulation of ADRB2 expression is associated with small cell neuroendocrine prostate cancer and adverse clinical outcomes in castration-resistant prostate cancer. Urologic Oncology: Seminars and Original Investigations. https://doi.org/10.1016/j.urolonc.2020.06.002