Abstract
Simple SummaryTreatment-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.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.
Highlights
An acquired drug resistance occurs in prostate cancer after treatments with nextgeneration androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide (ENZ)
Upregulation and amplification of N-Myc is detected in 40% of NEPC tumors whereas it is present in only 5% of prostate adenocarcinoma tumors suggesting that N-Myc contributes to the development of NEPC [33]
Future studies are needed to understand whether AR has similar effects in neuron-like Treatment-induced neuroendocrine prostate cancer (t-NEPC) phenotype as in neurons, which molecular mechanisms contribute the phenotypic plasticity in t-NEPC cells and whether these phenomena have any role in maintaining treatment resistance in prostate cancer
Summary
An acquired drug resistance occurs in prostate cancer after treatments with nextgeneration androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide (ENZ). ASCL1 was reported to directly reprogram and induce a phenotype switch of somatic stem cells to functional neurons either alone or in combination with SOX2 and NEUROG2 suggesting that similar reprogramming may occur in prostate neuroendocrine lineage reprogramming [34,67]. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function in pulmonary neuroendocrine tumors, a phenomenon which may occur in prostate cancer [15]
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