Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

SIMPLE SUMMARY: Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a subtype of castration-resistant prostate cancer (CRPC) which develops under prolonged androgen deprivation therapy. The mechanisms and pathways underlying the t-NEPC are still poorly understood and there are no effective treatments available. Here, we summarize the literature on the molecules and pathways contributing to neuroendocrine phenotype in prostate cancer in the context of their known cellular neurodevelopmental processes. We also discuss the role of tumor microenvironment in neuroendocrine plasticity, future directions, and therapeutic options under clinical investigation for neuroendocrine prostate cancer. ABSTRACT: Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.