1986PDHORAS5 promotes cabazitaxel resistance in castration resistant prostate cancer via a BCL2A1-dependent survival mechanism

Background: Long non-coding RNAs (lncRNAs) have been recently identified as key players in several cancer-associated pathways such as metastasis and drug resistance. Emerging evidence indicates that the HORAS5 lncRNA (i.e. linc00161) modulates drug response in different malignancies. In a recently published study, we have shown that HORAS5 promotes the survival of androgen receptor-positive (AR+) castration resistant prostate cancer (CRPC) cells. Preliminary data obtained in our lab show that HORAS5 is involved in response to cabazitaxel, in both AR+ and AR- CRPC cells. Methods: HORAS5 expression was modulated in AR+ and AR- CRPC cells with lentiviral-mediated overexpression and siRNA-based silencing. We measured cell count (Trypan Blue exclusion test) and apoptosis (caspase 3/7) of CRPC cells exposed to clinically achievable concentrations of cabazitaxel. RNA sequencing, RT-qPCR and western blot were used to identify genes regulated by HORAS5 in cabazitaxel-treated cells. We also transfected the cells with antisense oligonucleotides (ASOs), a technology that is currently being tested in clinical trials. Results: Our results show that HORAS5 overexpression increases cabazitaxel IC50 (p = 0.01), while HORAS5 silencing has an opposite effect (p = 0.003). HORAS5 also inhibits caspase activity upon cabazitaxel treatment (p Conclusions: Our findings show that HORAS5 mediates cabazitaxel resistance in both AR+ and AR- CRPC cells via regulation of the anti-apoptotic BCL2A1. Experiments with ASOs demonstrate the translational potential of HORAS5 inhibition. We are currently assessing HORAS5 expression in biological fluids from patients exposed (or not) to cabazitaxel. Legal entity responsible for the study: Francesco Crea. Funding: The Open University. Disclosure: All authors have declared no conflicts of interest.