Co-expression and clinical utility of AR-FL and AR splice variants AR-V3, AR-V7 and AR-V9 in prostate cancer

Neele Wüstmann; Konstantin Seitzer; Verena Humberg; Julia Vieler; Norbert Grundmann; Julie Steinestel; Dorothee Tiedje; Stefan Duensing; Laura-Maria Krabbe; Martin Bögemann; Andres Jan Schrader; Christof Bernemann; Katrin Schlack

doi:10.1186/s40364-023-00481-w

Co-expression and clinical utility of AR-FL and AR splice variants AR-V3, AR-V7 and AR-V9 in prostate cancer

Biomark Res. 2023 Apr 5;11(1):37. doi: 10.1186/s40364-023-00481-w.

Affiliations

¹ Department of Urology, University Hospital Muenster, Albert-Schweitzer Campus 1 A1, 48149, Muenster, Germany.
² Institute for Bioinformatics, University Hospital Muenster, Muenster, Germany.
³ Department of Urology, University Hospital Augsburg, Augsburg, Germany.
⁴ Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
⁵ Department of Urology, University Hospital Muenster, Albert-Schweitzer Campus 1 A1, 48149, Muenster, Germany. [email protected].

^# Contributed equally.

Abstract

Background: Androgen receptor (AR) splice variants (AR-Vs) have been discussed as a biomarker in prostate cancer (PC). However, some reports question the predictive property of AR-Vs. From a mechanistic perspective, the connection between AR full length (AR-FL) and AR-Vs is not fully understood. Here, we aimed to investigate the dependence of AR-FL and AR-V expression levels on AR gene activity. Additionally, we intended to comprehensively analyze presence of AR-FL and three clinically relevant AR-Vs (AR-V3, AR-V7 and AR-V9) in different stages of disease, especially with respect to clinical utility in PC patients undergoing AR targeted agent (ARTA) treatment.

Methods: AR-FL and AR-V levels were analyzed in PC and non-PC cell lines upon artificial increase of AR pre-mRNA using either drug treatment or AR gene activation. Furthermore, expression of AR-FL and AR-Vs was determined in PC specimen at distinct stages of disease (primary (n = 10) and metastatic tissues (n = 20), liquid biopsy samples (n = 422), mCRPC liquid biopsy samples of n = 96 patients starting novel treatment). Finally, baseline AR-FL and AR-V status was correlated with clinical outcome in a defined cohort of n = 65 mCRPC patients undergoing ARTA treatment.

Results: We revealed rising levels of AR-FL accompanied with appearance and increase of AR-Vs in dependence of elevated AR pre-mRNA levels. We also noticed increase in AR-FL and AR-V levels throughout disease progression. AR-V expression was always associated with high AR-FL levels without any sample being solely AR-V positive. In patients undergoing ARTA treatment, AR-FL did show prognostic, yet not predictive validity. Additionally, we observed a substantial clinical response to ARTA treatment even in AR-V positive patients. Accordingly, multivariate analysis did not demonstrate independent significance of AR-Vs in neither predictive nor prognostic clinical utility.

Conclusion: We demonstrate a correlation between AR-FL and AR-V expression during PC progression; with AR-V expression being a side-effect of elevated AR pre-mRNA levels. Clinically, AR-V positivity relies on high levels of AR-FL, making cells still vulnerable to ARTA treatment, as demonstrated by AR-FL and AR-V positive patients responding to ARTA treatment. Thus, AR-FL and AR-V might be considered as a prognostic, yet not predictive biomarker in mCRPC patients.

Keywords: Androgen receptor; Androgen receptor splice variants; Androgen receptor targeted agents; Biomarker; Circulating tumor cells; Liquid biopsy; Metastatic castration resistant prostate cancer; Predictive; Prognostic.