Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer
Citations Over TimeTop 1% of 2016 papers
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.
Related Papers
- → AR aberrations and resistance to abiraterone or enzalutamide(2016)45 cited
- → Comparison of Toxicity and Efficacy Outcomes of Abiraterone and Enzalutamide in 198 Patients with Metastatic Castrate Resistant Prostate Cancer(2017)7 cited
- → Germline DNA-repair Gene Mutations and Efficacy of Abiraterone or Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer(2019)1 cited
- Current understanding of resistance to abiraterone and enzalutamide in advanced prostate cancer.(2016)
- → 583P Baseline plasma tumour DNA (ptDNA) correlates with PSA kinetics in metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide(2021)