Therapeutic strategies for metastatic
castration-resistant
prostate cancer aim to target
androgen receptor signaling. Despite initial survival benefits, treatment resistance invariably occurs, leading to lethal disease.
Therapies targeting the
androgen receptor can induce the emergence of a neuroendocrine phenotype and reactivate embryonic programs associated with epithelial to mesenchymal transition. We recently reported that dysregulation of the
calcium signal can induce the
transcription factor Zeb1, a key determinant of cell plasticity during
tumor progression. The aim of this study was to determine whether the
androgen receptor-targeted treatment
Enzalutamide could induce dysregulation of the
calcium signal involved in the progression toward epithelial to mesenchymal transition and neuroendocrine differentiation, contributing to therapeutic escape. Our results show that Zeb1 and the SK3
potassium channel are overexpressed in vivo in neuroendocrine
castration-resistant
prostate cancer and in vitro in LNCaP cells neurodifferentiated after
Enzalutamide treatment. Moreover, the neuroendocrine phenotype is associated with a deregulation of the expression of Orai
calcium channels. We showed that Zeb1 and SK3 are critical drivers of neuroendocrine differentiation. Interestingly,
Ohmline, an SK3 inhibitor, can prevent the expression of Zeb1 and neuroendocrine markers induced by
Enzalutamide. This study offers new perspectives to increase
hormone therapy efficacy and improve clinical outcomes.