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

Christine Henzler, Yingming Li, Rendong Yang, Terri McBride, Yeung Ho, Cynthia Sprenger, Gang Liu, Ilsa Coleman, Bryce Lakely, Rui Li, Shihong Ma, Sean R. Landman, Vipin Kumar, Tae Hyun Hwang, Ganesh V. Raj, Celestia S. Higano, Colm Morrissey, Peter S. Nelson, Stephen R. Plymate, Scott M. Dehm

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65 Scopus citations

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.

Original languageEnglish (US)
Article number13668
JournalNature Communications
Volume7
DOIs
StatePublished - Nov 29 2016

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Henzler, C., Li, Y., Yang, R., McBride, T., Ho, Y., Sprenger, C., Liu, G., Coleman, I., Lakely, B., Li, R., Ma, S., Landman, S. R., Kumar, V., Hwang, T. H., Raj, G. V., Higano, C. S., Morrissey, C., Nelson, P. S., Plymate, S. R., & Dehm, S. M. (2016). Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nature Communications, 7, [13668]. https://doi.org/10.1038/ncomms13668