ADRB2 expression in progressive metastatic castration-resistant prostate cancer.

Abstract

145 Background: The net oncogenic effect of the G protein-coupled receptor β2 adrenergic receptor ADRB2, which may induce neuroendocrine differentiation via cyclic AMP and protein kinase A and whose expression is epigenetically regulated by EZH2, is controversial. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: This was a retrospective analysis of a cohort of men with mCRPC who were prospectively enrolled in the multi-center SU2C/PCF/AACR West Coast Prostate Cancer Dream Team study, in which biopsies of a metastatic site were obtained at disease progression. Specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and transcriptional cluster based on prior unsupervised hierarchical transcriptome clustering, and correlated with EZH2 expression. ADRB2 expression (lowest quartile) was correlated with OS from time of biopsy by log rank test and a multivariable Cox proportional hazard model. Results: One-hundred and twenty-seven men with progressive mCRPC underwent metastatic biopsies and had sufficient tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P<0.001), and correlated inversely with EZH2 expression (r=-0.28, P<0.01). Men with low ADRB2 expression had a shorter median OS than those with high (9.5 vs 18.9 mo, P=0.02). In multivariable analysis adjusting for small cell histology, performance status, LDH, and visceral metastases, high ADRB2 expression was associated with a trend towards longer OS (HR=0.65, 95% CI 0.41-1.02, P=0.06). Conclusions: Low ADRB2 expression is associated with worse OS in men with progressive mCRPC, and may be a means by which EZH2 confers resistance to antiandrogen therapy. Indirect ADRB2 stimulation with EZH2 inhibitors may improve outcomes. Validation in independent cohorts is necessary.