Abstract 1972P
Background
In the AFFIRM phase III clinical trial of enzalutamide, an androgen receptor (AR) signalling inhibitor, has been shown to significantly increase survival in patients with metastatic castration resistant prostate cancer, however, intrinsic and acquired resistance are substantial clinical predicaments. Although a number of resistance mechanisms have been described, enzalutamide resistance has yet to be fully understood. Circular RNAs (circRNAs) are a novel type of non-coding RNA that may play an important role in cancer development and drug resistance. The aim of this study was to examine the role of circRNA in enzalutamide resistant prostate cancer.
Methods
The enzalutamide cell line model consisted of age matched LNCaP parental cells (Control) and two sub-lines displaying high (Clone 1) and weak (Clone 9) drug resistance. circRNA profiling was performed on the cell line panel using a high throughput microarray (Arraystar). Bioinformatic analysis identified a number of differentially expressed circRNAs and their putative parental genes. These were validated using qPCR. circRNAs were stably overexpressed in the Control cell line, and the effect of enzalutamide treatment was assessed using an ELISA based proliferation assay.
Results
hsa_circ_0001275 and its’ parental gene, PLCL2, were significantly up regulated in Clone 1 vs. Control and Clone 9 vs. Control (p<0.05). hsa_circ_0000129 was also significantly up regulated in Clone 1 vs. Control (p<0.05), however the associated parental gene VPS72 showed no significant difference. hsa_circ_0001721 was previously identified as upregulated in Clone 1 vs. Control (p<0.05). Overexpression of hsa_circ_0001721, resulted in increased drug resistance in the control cell line (p<0.05).
Conclusions
Our circRNA microarray analysis demonstrated a differential pattern of circRNA expression within the isogenic model of enzalutamide resistance. Proliferation data suggests that increased levels of hsa_circ_0001721 contributes to enzalutamide resistance. While work is ongoing to further delineate the circRNA-miRNA-mRNA landscape in prostate cancer, data suggests that circRNAs hold potential as valuable clinical biomarkers for personalised therapy in this disease.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Prostate Cancer Foundation Young Investigator Award (S.F) and The Irish Cancer Society (S.F).
Disclosure
All authors have declared no conflicts of interest.