Pilot: PLK1 Phosphorylation of NEUROD1 in Prostate Cancer Lineage Plasticity

Since androgen receptor (AR) is essential for development of prostate cancer (PCa), including castration- resistant prostate cancer (CRPC), androgen signaling inhibitors (ASI) such as enzalutamide are becoming the first line treatment for CRPC. Unfortunately, enzalutamide treatment causes the transdifferentiation of epithelial luminal cells into basal, stem-like and neuroendocrine cells, resulting in enzalutamide resistance. Therefore, understanding PCa lineage plasticity will identify targets/pathways whose inhibition might potentially reverse treatment-induced transdifferentiation back to AR-dependent adenocarcinoma, rendering cancer cells to be sensitive to enzalutamide again. The progression from CRPC to neuroendocrine cancer (NEPC) is mainly driven by transcription / epigenetic regulation. NEUROD1 (Neurogenic Differentiation 1) is a transcriptional factor that is recently reported to be involved in the lineage plasticity of PCa. However, how NEUROD1 is regulated to promote lineage plasticity is largely unknown. The objective is to define the role of polo-like kinase 1 (PLK1) in regulating NEUROD1 during PCa lineage plasticity. The central hypothesis is that PLK1-mediated phosphorylation of NEUROD1 drives lineage plasticity in PCa, and that inhibition of PLK1 reverses the neuronal transdifferentiation process back to AR-dependent adenocarcinoma, rendering cancer cells to be sensitive to enzalutamide again. Our data show that PLK1 is elevated in NEPC in comparison to CRPC and that PLK1 phosphorylation of NEUROD1 promotes lineage plasticity in PCa. Our hypothesis will be tested by pursuing three Aims - (1) to examine how CDK1 and PLK1 sequentially phosphorylates NEUROD1; (2) to determine the function of PLK1 phosphorylation of NEUROD1 in PCa lineage plasticity; (3) to investigate whether PLK1 inhibition renders NEPC to be sensitive to enzalutamide. Study Design These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing culture systems and mouse models. The rationale for the research is that it will probe the importance of PLK1 in PCa lineage plasticity. This contribution is significant because, if positive, the results of the proposed study will support an immediate clinical trial for PLK1 inhibitor plus enzalutamide to treat NEPC.