Neuroendocrine prostate cancer (NEPC) is a lethal subset of metastatic castration-resistant prostate cancer (mCRPC) with aggressive clinical features and poor overall survival. Although rarely occurs de novo, the treatment-related NEPC (t-NEPC) derived from prostatic adenocarcinoma (PAC) can arise in about 25% or more late stage mCRPC, which is notoriously hard to treat and resistant to antiandrogen therapy. There is an urgent need for novel targets and therapies. In this study, we seek to determine the roles of PKD in t-NEPC and exploit the therapeutic potential of PKD inhibitors for the treatment of t-NEPC. PRKDs were amplified and/or upregulated in nearly 60% of NEPC tumors. PKD, particularly PKD2, protein expression and activity were elevated in NEPC tumor tissues. Knockdown of PKD2/3, the predominant PKDs in NEPC cells, decreased NE biomarkers, inhibited cell proliferation/survival, and tumor growth in vivo, while PKD2 overexpression promoted NE programing by inducing NE markers and suppressing AR-targeted genes, which paralleled the effects of N-myc, a major driver of NEPC. Overexpression of PKD2 also conferred androgen independence and reduced sensitivity to chemotherapeutic agents in in androgen-sensitive PAC cells. We further identified AURKA/Aurora-A kinase as a novel downstream target of PKD. Aurora-A, a key mitotic regulator that is co-amplified and upregulated with N-myc in NEPC tumors, promotes NEPC progression by binding and stabilizing N-myc. Our data indicated that PKD activity was required for the stabilization of Aurora-A/N-myc complex. Overexpression of PKD phenocopied, while knockdown of PKD blocked, the functions of N-myc in prostate cancer cells, implying a role of PKD in regulating Aurora-A/N-myc complex. Moreover, the stabilization of Aurora-A by PKD is necessary for mitotic entry, a function that may contribute to taxane-based therapy resistance. Importantly, inhibition of PKD by the PKD inhibitor CRT0066101 (CRT) blocked NEPC tumor cell proliferation/survival, migration/invasion, and suppressed the growth of NEPC tumor xenografts and reduced bone metastasis in vivo. CRT also synergized with docetaxel and PI3K inhibitor in NEPC cells, implying their potential use in combination therapy. Based on these findings, we hypothesize that increased PKD expression and activity promote mitotic programing and Aurora-A/N-myc complex stability to impinge upon N- myc-driven t-NEPC progression. We further posit that PKD inhibitors will derive a new therapeutic strategy to better treat NEPC. We propose to: Aim 1. Determine PKD as a potential biomarker for t-NEPC and assess the functional relevance of PKD-activated mitotic programing to therapeutic resistance in t-NEPC. Aim 2. Test the hypothesis that PKD promotes t-NEPC by stabilizing Aurora-A/N-myc complex to impinge upon N-myc-driven oncogenesis. Aim 3. Determine the therapeutic potential of PKD inhibitors for treatment of NEPC in a metastatic NEPC mouse model and TRAMP mice.