The role of focal adhesion kinase in therapy resistant prostate tumors

粘着斑激酶在治疗耐药性前列腺肿瘤中的作用

• 批准号: 10638034
• 负责人: Xuesen Dong
• 金额: $ 45.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638034
• 关键词: Adenocarcinoma; Adenocarcinoma Cell; Affinity Chromatography; Alternative Splicing; Androgen Receptor; Biological Assay; Cancer Cell Growth; Cancer Patient; Cell Proliferation; Cell Survival; Cells; Clinical; Combined Modality Therapy; Complex; Degradation Pathway; Development; Disease; Epigenetic Process; Exons; Focal Adhesion Kinase 1; Generations; Genes; Genomics; Goals; Growth; Histology; Hypoxia; Immunohistochemistry; In Situ Hybridization; Invaded; Knowledge; Label; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Molecular; Neoplasm Metastasis; Nerve Block; Neuroendocrine Carcinoma; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Oncogenes; Oncogenic; Outcome; Oxidative Stress; Palliative Care; Pathway interactions; Patient-Focused Outcomes; Patients; Peroxidases; Pharmaceutical Preparations; Phase I/II Clinical Trial; Phosphotransferases; Prostate Adenocarcinoma; Prostatic Neoplasms; Protein Biosynthesis; Protein Kinase; Proteomics; RNA; RNA Splicing; Reagent; Receptor Signaling; Reporting; Resistance; Role; Sampling; Signal Transduction; Spliced Genes; Stress; Subgroup; Techniques; Technology; Testing; Therapeutic; Tumor Promotion; Variant; Xenograft procedure; anti-cancer; ascorbate; cancer cell; cancer stem cell; castration resistant prostate cancer; chemotherapy; clinically relevant; cohort; gene product; genome-wide; improved; insight; kinase inhibitor; nanopore; neoplastic cell; neural; neuroendocrine differentiation; novel therapeutics; patient derived xenograft model; phosphoproteomics; programs; prostate cancer cell; prostate cancer progression; protein degradation; protein expression; targeted treatment; therapy development; therapy resistant; transcription factor; transcriptome; transcriptome sequencing; tumor; tumor growth

Abstract Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a subgroup of prostate tumors with poor patient outcomes. Beyond systemic chemotherapy and palliative care, no targeted therapy has been successful reflecting our limited knowledge of how NEPC is developed. We have reported a t-NEPC-specific RNA splicing program driven by the neural splicing factor SRRM4, which promotes t-NEPC development. This splicing program has genome-wide impacts on cancer cells as it reprograms the functions of epigenetic modulators, transcriptional factors, and cancer stem cell regulators, resulting in prostate adenocarcinoma cells acquiring neuroendocrine lineage and becoming independent of AR signalling for survival. The FAK (focal adhesion kinase) gene splicing is a part of the t-NEPC splicing program, whereby neural FAK splice variants are highly expressed in t-NEPC. In contrast to the constitutive FAK (FAK-c) splice variant, neural FAKs promote neuroendocrine differentiation and AR-independent tumor growth. Further RNA-seq analysis indicated that these neural FAKs act mainly through a hypoxic transcriptome via HIF-1. Importantly, we found that when tumor cells gain the neural FAK signaling, they become vulnerable to FAK kinase inhibitors. These findings suggest that aberrant RNA splicing of the FAK gene promotes t-NEPC progression and that targeting the FAK signal may provide a new therapeutic option for t-NEPC patients. We have developed four specific aims to test this hypothesis. In Aim 1, we will establish the clinical relevance of neural FAK splicing in association with neuroendocrine carcinoma histology, castrate-resistant prostate cancer progression, tumor metastasis, and patient clinical outcomes. In Aim 2, we will decipher the intrinsic mechanism by which SRRM4 regulates neural FAK splicing, and determine the extrinsic therapy-induced stress conditions that regulate RNA splicing of neural FAKs. In Aim 3, we will characterize several FAK-associated kinase signaling that were known to enhance HIF-1 protein expression through either protein synthesis or protein degradation pathways. We will also employ global proteomic analyses to profile neural FAK interactomes and their activated phosphor- proteomics that promote t-NEPC progression. In Aim 4, we will study whether FAK inhibitors can block neural FAK actions in NEPC cells and test whether FAK inhibitors can be used as a combination therapy to block t- NEPC xenograft growth. In summary, these studies will gain new mechanistic insight into how prostate cancer cells develop therapy- resistance and nominate FAK inhibitors to be potential therapeutics for therapy-resistant prostate tumors.

摘要 治疗诱导的神经内分泌前列腺癌（t-NEPC）是前列腺肿瘤的一个亚组， 成果。除了全身化疗和姑息治疗，没有靶向治疗成功 反映出我们对NEPC如何发展的了解有限。 我们已经报道了一个由神经剪接因子SRRM 4驱动的t-NEPC特异性RNA剪接程序， 促进t-NEPC的发展。这种剪接程序对癌细胞具有全基因组的影响，因为它 重新编程表观遗传调节因子、转录因子和癌症干细胞调节因子的功能， 导致前列腺癌细胞获得神经内分泌谱系并变得不依赖于AR 生存的信号。FAK（粘着斑激酶）基因剪接是t-NEPC剪接程序的一部分， 由此神经FAK剪接变体在t-NEPC中高度表达。与组成型FAK（FAK-c）相比， 剪接变体，神经FAK促进神经内分泌分化和AR非依赖性肿瘤生长。进一步 RNA-seq分析表明，这些神经FAK主要通过HIF-1 α通过缺氧转录组起作用。 重要的是，我们发现当肿瘤细胞获得神经FAK信号时，它们变得对FAK敏感 激酶抑制剂。 这些发现表明FAK基因的RNA剪接异常促进t-NEPC的进展， 靶向FAK信号可能为t-NEPC患者提供新的治疗选择。我们开发了四个 具体目的是检验这一假设。在目标1中，我们将建立神经FAK剪接的临床相关性， 与神经内分泌癌组织学、去势抵抗性前列腺癌进展、肿瘤 转移和患者临床结果。在目标2中，我们将破译SRRM 4 调节神经FAK剪接，并确定调节RNA的外源性治疗诱导的应激条件 神经FAKs的拼接在目标3中，我们将描述几种已知的FAK相关激酶信号传导， 通过蛋白质合成或蛋白质降解途径增强HIF-1 α蛋白表达。我们将 还采用全球蛋白质组学分析来描绘神经FAK相互作用组及其活化的磷， 促进t-NEPC进展的蛋白质组学。在目的4中，我们将研究FAK抑制剂是否可以阻断神经细胞， FAK在NEPC细胞中的作用，并测试FAK抑制剂是否可用作联合疗法来阻断t- NEPC异种移植物生长。 总之，这些研究将获得前列腺癌细胞如何发展治疗的新机制见解- 并提名FAK抑制剂为治疗抗性前列腺肿瘤的潜在治疗剂。