# A novel mitotic regulatory axis in neuroendocrine prostate cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $358,483

## Abstract

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.

## Key facts

- **NIH application ID:** 10197021
- **Project number:** 5R01CA229431-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Qiming Jane Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,483
- **Award type:** 5
- **Project period:** 2019-07-02 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197021

## Citation

> US National Institutes of Health, RePORTER application 10197021, A novel mitotic regulatory axis in neuroendocrine prostate cancer (5R01CA229431-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197021. Licensed CC0.

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