A novel mitotic regulatory axis in neuroendocrine prostate cancer

神经内分泌前列腺癌中的新型有丝分裂调节轴

• 批准号: 10636919
• 负责人: Qiming Jane Wang
• 金额: $ 35.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-02 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10636919
• 关键词: Adenocarcinoma Cell; American; Androgens; Antiandrogen Therapy; Binding; Biological Markers; Cancer Etiology; Castration; Cell Proliferation; Cessation of life; Clinical; Combined Modality Therapy; Complex; Data; Disease; F-Box Proteins; Family; Genes; Growth; Inhibition of Cell Proliferation; Invaded; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Microtubules; Mitotic; Neuroendocrine Prostate Cancer; Neurosecretory Systems; PIK3CG gene; Pathogenesis; Pathway interactions; Patients; Phenocopy; Phosphotransferases; Process; Prostate Adenocarcinoma; Prostatic Neoplasms; Resistance; Role; Signal Transduction; Testing; Therapeutic; Treatment Efficacy; Tumor Tissue; Ubiquitin; Up-Regulation; androgen deprivation therapy; androgen sensitive; anticancer activity; aurora kinase A; castration resistant prostate cancer; chemotherapeutic agent; diagnostic value; docetaxel; effective therapy; in vivo; inhibitor; insight; knock-down; member; men; migration; mortality; mouse model; multicatalytic endopeptidase complex; neoplastic cell; neuroendocrine differentiation; new therapeutic target; novel; novel therapeutic intervention; overexpression; potential biomarker; prognostic value; prostate cancer cell; prostate cancer progression; protein expression; protein kinase D; relapse patients; resistance mechanism; response; synergism; targeted agent; targeted treatment; taxane; therapeutic development; therapeutic target; therapy development; therapy resistant; transgenic adenocarcinoma of mouse prostate; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis; virtual

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.

神经内分泌前列腺癌（NEPC）是转移性cast割前列腺癌的致命子集 （MCRPC）具有积极的临床特征和整体生存率差。虽然很少发生从头开始 从前列腺腺癌（PAC）衍生的与治疗相关的NEPC（T-NEPC）可能出现约25％或更多 后期MCRPC，众所周知，很难治疗并抗抗杀菌疗法。有紧急 需要新颖的目标和疗法。在这项研究中，我们试图确定PKD在T-NEPC中的作用并利用 PKD抑制剂治疗T-NEPC的治疗潜力。 PRKD被放大和/或上调 在近60％的NEPC肿瘤中。 NEPC中PKD，尤其是PKD2，蛋白质表达和活性升高 肿瘤组织。 NEPC细胞中主要的PKD的PKD2/3的敲低降低了NE生物标志物，抑制了 细胞增殖/存活和体内肿瘤生长，而PKD2过表达促进了NE编程 诱导NE标记和抑制AR靶向基因，该基因与N-MYC的影响（主要驱动器）的作用并联 NEPC。 PKD2的过表达也赋予了雄激素独立性，并降低了对 雄激素敏感PAC细胞中的化学治疗剂。我们进一步将Aurka/Aurora-A激酶视为 PKD的新型下游目标。 Aurora-a，一种关键有丝分裂调节剂，与 NEPC肿瘤中的N-MYC通过结合和稳定N-MYC促进NEPC进展。我们的数据表明 稳定Aurora-A/N-MYC复合物需要PKD活性。 PKD表达的过表达， 当PKD敲低时，N-MYC在前列腺癌细胞中的功能，这意味着PKD在 调节Aurora-A/N-MYC复合物。此外，有丝分裂需要通过PKD稳定Aurora-A 条目，可能有助于基于紫杉烷的治疗抗性的功能。重要的是，抑制PKD PKD抑制剂CRT0066101（CRT）阻止NEPC肿瘤细胞增殖/生存，迁移/侵袭和 抑制了NEPC肿瘤异种移植物的生长，并减少了体内骨转移。 CRT也协同作用 NEPC细胞中的多西他赛和PI3K抑制剂，这意味着它们在联合疗法中的潜在用途。基于 这些发现，我们假设PKD表达和活性增加了有丝分裂编程 以及Aurora-A/N-MYC复合稳定性，以影响N- MYC驱动的T-NEPC进展。我们进一步 假定PKD抑制剂将得出一种更好的治疗NEPC的新治疗策略。我们建议：目标 1。确定PKD作为T-NEPC的潜在生物标志物，并评估PKD激活的功能相关性 T-NEPC中的有丝分裂编程针对治疗性抗性。 AIM 2。检验PKD促进T-NEPC的假设 通过稳定Aurora-A/N-MYC复合物以构成N-MYC驱动的肿瘤发生。目标3。确定 PKD抑制剂在转移性NEPC小鼠模型和流浪汉中治疗NEPC的治疗潜力 老鼠。

项目成果

Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases.

• DOI: 10.3390/biom11030483
• 发表时间: 2021-03-23
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Zhang X;Connelly J;Chao Y;Wang QJ
• 通讯作者: Wang QJ

Small Molecule Inhibitors of Protein Kinase D: Early Development, Current Approaches, and Future Directions.

• DOI: 10.1021/acs.jmedchem.2c01599
• 发表时间: 2023-01-12
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Wang, Qiming Jane;Wipf, Peter
• 通讯作者: Wipf, Peter

Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner.

蛋白激酶 D2 和 D3 通过以 MEK/ERK1/2 依赖性方式正向调节 Runx2 促进前列腺癌细胞骨转移。

• DOI: 10.1016/j.ajpath.2023.01.004
• 发表时间: 2023
• 期刊: The American journal of pathology
• 作者: Roy,Adhiraj;Prasad,Sahdeo;Chen,Yuzhou;Chao,Yapeng;Liu,Yu;Zhao,Jinjun;Wang,QimingJane
• 通讯作者: Wang,QimingJane