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

Journal Article (Journal Article;Multicenter Study)

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.

Full Text

Duke Authors

Cited Authors

  • Kwon, DH; Zhang, L; Quigley, DA; Foye, A; Chen, WS; Wong, CK; Feng, FY; Bailey, A; Huang, J; Stuart, JM; Friedl, V; Weinstein, AS; Beer, TM; Alumkal, JJ; Rettig, M; Gleave, M; Lara, PN; Thomas, GV; Li, P; Lui, A; Small, EJ; Aggarwal, RR

Published Date

  • December 2020

Published In

Volume / Issue

  • 38 / 12

Start / End Page

  • 931.e9 - 931.e16

PubMed ID

  • 32624423

Electronic International Standard Serial Number (EISSN)

  • 1873-2496

Digital Object Identifier (DOI)

  • 10.1016/j.urolonc.2020.06.002

Language

  • eng

Conference Location

  • United States