Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer.

Abstract:

:Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.

journal_name

Nat Commun

journal_title

Nature communications

authors

Henzler C,Li Y,Yang R,McBride T,Ho Y,Sprenger C,Liu G,Coleman I,Lakely B,Li R,Ma S,Landman SR,Kumar V,Hwang TH,Raj GV,Higano CS,Morrissey C,Nelson PS,Plymate SR,Dehm SM

doi

10.1038/ncomms13668

subject

Has Abstract

pub_date

2016-11-29 00:00:00

pages

13668

issn

2041-1723

pii

ncomms13668

journal_volume

7

pub_type

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