Abstract
Simple SummaryAlthough newer generations of androgen deprivation therapy such as enzalutamide are providing hope, it is clinically challenging to deliver effective therapy to individuals with metastatic castrate-resistant prostate cancer. Between 20–40% of patients have intrinsic resistance to therapy and all patients will ultimately experience disease progression due to acquired resistance, which is a significant clinical dilemma. The aim of our study was to evaluate the role of circular RNAs (circRNAs) in enzalutamide-resistant prostate cancer as part of the effort to identify useful biomarkers for patient selection and potential new therapeutic targets. We confirmed that hsa_circ_0001275 was highly upregulated in an enzalutamide resistant cell line and demonstrated that its overexpression resulted in increased enzalutamide resistance. Our data showed that hsa_circ_0001275 was not expressed abundantly in patient plasma samples, however, a trend of expression was evident which paralleled disease activity indicating a possible association with enzalutamide resistance. Overall, we have provided evidence that hsa_circ_0001275 promotes enzalutamide resistance and thus may serve as a potential therapeutic target.Background: Enzalutamide is part of the treatment regimen for metastatic castration-resistant prostate cancer (MCRPC). However, both intrinsic and acquired resistance to the drug remain substantial clinical quandaries. circRNAs, a novel type of non-coding RNA, have been identified in a number of cancers including prostate cancer and have been associated with cancer development and progression. circRNAs have shown great potential as clinically useful blood-based ‘liquid biopsies’ and as therapeutic targets in prostate cancer. The aim of this study was to examine the role of circRNA transcripts in enzalutamide-resistant prostate cancer cells and assess their utility as biomarkers. Methods: An isogenic cell line model of enzalutamide resistance was subjected to circRNA microarray profiling. Several differentially expressed circRNAs, along with their putative parental genes were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). circRNAs of interest were stably overexpressed in the control cell line and drug sensitivity was assessed using an ELISA-based proliferation assay. The candidate circRNA, hsa_circ_0001275, was measured in patient plasma samples using RT-droplet digital PCR (RT-ddPCR). Results: hsa_circ_0001275 and its parental gene, PLCL2, were significantly up-regulated in strongly resistant clones vs. control (p < 0.05). Overexpression of hsa_circ_0001275 in the control cell line resulted in increased resistance to enzalutamide (p < 0.05). While RT-ddPCR analysis of hsa_circ_0001275 expression in plasma samples of 44 clinical trial participants showed a trend that mirrored the stages of disease activity (as defined by PSA level), the association did not reach statistical significance. Conclusions: Our data suggest that increased levels of hsa_circ_0001275 contribute to enzalutamide resistance. hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance.
Highlights
Prostate cancer is the most common invasive cancer diagnosed in men and the second leading cause of male cancer-associated mortality in the United States (US) [1]
In order to further investigate the value of circRNA as a biomarker to inform drug resistance, we, investigated the level of hsa_circ_0001275 in plasma samples of clinical trial (CTRIAL-IE 13-21, NCT02225704) patients with prostate cancer on enzalutamide treatment via RT-ddPCR. These results suggested a trend that corresponded to the activity of the disease defined by the PSA level of patients on enzalutamide treatment, it did not reach statistical significance likely due to small cohorts and/or copy numbers were close to the limit of detection for RT-ddPCR
We found hsa_circ_0001275 up-regulated in enzalutamide-resistant cell lines with data suggesting a protective role against enzalutamide in vitro
Summary
Prostate cancer is the most common invasive cancer diagnosed in men and the second leading cause of male cancer-associated mortality in the United States (US) [1]. About 35% to 60% of men undergoing the initial curative effort will experience disease recurrence [4,5,6] For these patients, androgen deprivation therapy (ADT) is the standard of treatment [7] but resistance inevitably develops resulting in castration-resistant prostate cancer (CRPC), which is currently incurable [8]. While RT-ddPCR analysis of hsa_circ_0001275 expression in plasma samples of 44 clinical trial participants showed a trend that mirrored the stages of disease activity (as defined by PSA level), the association did not reach statistical significance. Hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance Conclusions: Our data suggest that increased levels of hsa_circ_0001275 contribute to enzalutamide resistance. hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance
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