Prostate cancer (PC) is the most commonly diagnosed male cancer both in the United States and in Europe. Approximately 20-25% of cases will develop metastatic disease, which eventually progresses to lethal castration-resistant form of the disease (CRPC). Even though the exact mechanism by which CRPC develops remains to be fully understood, several mechanisms of castration resistance have been identified. Importantly, androgen signaling remains active even in the CRPC stage. This has led to the clinical development of second-generation AR-targeting drugs enzalutamide and abiraterone that target the ligand-binding domain of AR directly and indirectly, respectively. Unfortunately, a significant subset of patients show primary resistance to these agents. One potential explanation for this is the presence of AR splice variants (AR-Vs). AR-Vs are alternatively spliced isoforms of the AR mRNA usually resulting in truncated AR protein product. Even though AR-Vs lack variable portions of the AR COOH-terminal domain including the ligand-binding domain (LBD), they are constitutively active as transcription factors. The aim of this work was to study AR-Vs and also AR rearrangements, mutations and copy number variations (CNVs) to better understand the emergence of CRPC. This was done by analyzing specimens from different stages of prostate cancer by next-generation sequencing methods. Our sample cohorts included hormone-naïve PCs and lymph node metastases as well as locally recurrent and metastatic CRPCs. AR mutations and CNVs were detected only in CRPC specimens. Genomic structural rearrangements of AR (AR-GSRs) were observed in 5/30 metastatic CRPC patients but they were not associated with the expression of previously known AR-Vs, and their variant allele fractions were low. The main AR-Vs detected were AR-V3, AR-V7 and AR-V9, whose expression levels were higher in CRPC cases in comparison to prostatectomy samples. The differences were statistically significant for either variant alone or when their expression fractions were combined (p=0.0006). In addition, metastatic CRPC cases expressed significantly more AR-V3, AR-V7 and AR-V9 when compared to non-androgen deprived pelvic lymph node metastases (p=0.0282). The expression of these AR-Vs was strongly associated with the levels of full-length AR. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harbored expression of all three of these AR-Vs. In conclusion, AR-V3, AR-V7 and AR-V9 tend to be co-expressed in metastatic CRPC highlighting the fact that targeting of the AR ligand-binding domain might not be sufficient to achieve a treatment response in certain patients. Consequently, targeting of AR via regions common to all AR-Vs is likely to provide additional benefit to patients suffering from CRPC.
Citation Format: Heini M. Kallio, Reija Hieta, Anniina Brofeldt, Matti Annala, Kati Kivinummi, Teuvo L. Tammela, Matti Nykter, William B. Isaacs, Hans G. Lilja, G Steven Bova, Tapio Visakorpi. Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1802.