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) 是转移性去势抵抗性前列腺癌的致命亚型 (mCRPC) 具有侵袭性临床特征和较差的总体生存率。尽管很少从头发生， 源自前列腺腺癌 (PAC) 的治疗相关 NEPC (t-NEPC) 的发生率约为 25% 或更多 晚期 mCRPC 众所周知很难治疗并且对抗雄激素治疗具有抵抗力。有紧急情况 需要新的靶点和疗法。在本研究中，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 被扩增和/或上调 近 60% 的 NEPC 肿瘤。 NEPC 中 PKD，特别是 PKD2，蛋白表达和活性升高 肿瘤组织。敲低 PKD2/3（NEPC 细胞中的主要 PKD）可减少 NE 生物标志物，抑制 细胞增殖/存活和体内肿瘤生长，而 PKD2 过表达通过以下方式促进 NE 编程： 诱导 NE 标记并抑制 AR 靶向基因，这与主要驱动因素 N-myc 的作用相似 国家能源委员会。 PKD2 的过度表达还赋予雄激素独立性并降低对雄激素的敏感性 雄激素敏感的 PAC 细胞中的化疗剂。我们进一步鉴定 AURKA/Aurora-A 激酶为 PKD 的一个新的下游靶点。 Aurora-A，一种关键的有丝分裂调节因子，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 Aurora-A/N-myc 复合物的稳定需要 PKD 活性。 PKD 表型过度表达， 当 PKD 的敲低被阻断时，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，PKD 稳定 Aurora-A 对于有丝分裂是必要的 进入，这一功能可能有助于紫杉烷类疗法的耐药性。重要的是，PKD 的抑制 PKD 抑制剂 CRT0066101 (CRT) 阻断 NEPC 肿瘤细胞增殖/存活、迁移/侵袭，并 抑制 NEPC 肿瘤异种移植物的生长并减少体内骨转移。 CRT也协同作用 在 NEPC 细胞中使用多西他赛和 PI3K 抑制剂，这意味着它们在联合治疗中的潜在用途。基于 根据这些发现，我们假设 PKD 表达和活性的增加促进有丝分裂编程 Aurora-A/N-myc 复合物稳定性影响 N-myc 驱动的 t-NEPC 进展。我们进一步 认为 PKD 抑制剂将衍生出一种新的治疗策略来更好地治疗 NEPC。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 有丝分裂编程对 t-NEPC 的治疗耐药性。目标 2. 检验 PKD 促进 t-NEPC 的假设 通过稳定 Aurora-A/N-myc 复合物来影响 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 TRAMP 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