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 Jr; George V Thomas; Patricia Li; Austin Lui; Eric J Small; Rahul R Aggarwal

doi:10.1016/j.urolonc.2020.06.002

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

Urol Oncol. 2020 Dec;38(12):931.e9-931.e16. doi: 10.1016/j.urolonc.2020.06.002. Epub 2020 Jul 2.

Authors

Daniel H Kwon¹, Li Zhang², David A Quigley³, Adam Foye¹, William S Chen⁴, Christopher K Wong⁵, Felix Y Feng⁶, Adina Bailey¹, Jiaoti Huang⁷, Joshua M Stuart⁵, Verena Friedl⁵, Alana S Weinstein⁵, Tomasz M Beer⁸, Joshi J Alumkal⁹, Matthew Rettig¹⁰, Martin Gleave¹¹, Primo N Lara Jr¹², George V Thomas¹³, Patricia Li¹⁴, Austin Lui¹⁴, Eric J Small¹, Rahul R Aggarwal¹⁵

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, CA.
² Department of Medicine, University of California, San Francisco, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
³ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.
⁴ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; Yale School of Medicine, New Haven, CT.
⁵ Department of Biomolecular Engineering and UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA.
⁶ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA.
⁷ Department of Pathology, Duke University, Durham, NC.
⁸ Department of Medicine, Oregon Health & Science University, Portland, OR.
⁹ Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
¹⁰ Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
¹¹ Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹² Department of Internal Medicine, University of California, Davis, Davis, CA.
¹³ Department of Pathology, Oregon Health & Science University, Portland, OR.
¹⁴ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
¹⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA. Electronic address: rahul.aggarwal@ucsf.edu.

PMID: 32624423
DOI: 10.1016/j.urolonc.2020.06.002

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.

Keywords: ADRB2; Beta adrenergic receptor; EZH2; Neuroendocrine; Prostate cancer.

Publication types

Multicenter Study

MeSH terms

Aged
Aged, 80 and over
Carcinoma, Neuroendocrine / genetics*
Carcinoma, Neuroendocrine / mortality
Carcinoma, Small Cell / genetics*
Carcinoma, Small Cell / mortality
Down-Regulation
Gene Expression Regulation, Neoplastic*
Humans
Male
Middle Aged
Prostatic Neoplasms, Castration-Resistant / genetics*
Prostatic Neoplasms, Castration-Resistant / mortality
Receptors, Adrenergic, beta-2
Retrospective Studies
Survival Rate

Substances

ADRB2 protein, human
Receptors, Adrenergic, beta-2