PO-445 The phenotypic plasticity of castration-resistant prostate cancer: from challenge to opportunity

Abstract

Introduction We have previously reported on the development of two in vitro models (PDB and MDB) of castration-resistant prostate cancer (CRPC) (Ferrari et al. Cell Comm Sign. 2017 8;15 (1:51). These cell lines are resistant to bicalutamide (BIC) and mimic effectively intermediate phases of CRPC. We investigated the effects of enzalutamide (ENZ) and docetaxel (DOC) on PDB and MDB and we assessed the prostate-specific antigen (PSA) and androgen receptor (AR) expression, during BIC treatment and after BIC discontinuation or exposure to 5-adihydrotestosterone (DHT). Material and methods The proliferative activity of PDB and MDB was assessed using the crystal violet assay at baseline (PDB control: 10 mM of BIC and 0.1 nM of DHT; MDB control: 10 mM of BIC), after BIC discontinuation and after DHT exposure (0.1 nM, MDB only). Cell proliferation and viability were also assessed at the same conditions after exposure to ENZ (1 mM) or to DOC (0.1 nM). Western blot analysis of PSA and AR expression was performed using anti-AR and anti-PSA antibodies. Two-tailed Student's t-test was used to calculate the p-values. Results and discussions After BIC discontinuation, DHT administration increased significantly the growth of the highly aggressive MDB cells and conferred them sensitivity to DOC. Under any condition, ENZ showed agonistic properties on MDB, rather than cytotoxic effects. The less aggressive PDB cells showed sensitivity to both DOC and ENZ during BIC administration, but not after BIC discontinuation. AR variants were not detected in our cell lines. AR and PSA showed dynamic expression, depending on type of cell line and BIC or DHT exposure. AR expression was not associated with PSA expression or with cell growth. The heterogeneous response of MDB and PDB to both DOC and ENZ properly mimics the variable response, observed in patients with CRPC, to hormonal and chemotherapeutic agents. Our results indicate that plasticity and rapid metabolic adaption contribute to CRPC cells survival in an androgen-deprived environment. Our preclinical evidences also suggest that androgen and antiandrogen administration might modulate AR activity and resistance to therapies in CRPC. Conclusion We demonstrated that AR and PSA expression are dynamic in antiandrogen-resistant cells and that response to both DOC and ENZA may depend on first-line antiandrogen and/or androgen administration. Further studies should investigate the molecular mechanisms underlying these findings.