Tyrosine Kinases and Prostate Cancer

摘要 这项名为“酪氨酸激酶与前列腺癌”的研究始于1998年，最初是随着酪氨酸的发展。 第一个全面的前列腺癌细胞酪氨酸激酶图谱。在 随后几年，酪氨酸激酶参与神经内分泌分化和雄激素非依赖性 并对过程进行了表征。这导致了一种酪氨酸激酶复合体的发现 SRC、ETK和FAK(称为Src激酶复合体)作为信号的中央积分器从 酪氨酸激酶受体、细胞因子受体和G蛋白偶联受体。这些酪氨酸激酶 提出潜在治疗干预的新靶点。目前的提案集中在前列腺癌上 肿瘤生物学和病因学，特别是Src/ETK酪氨酸激酶复合体在前列腺癌中的作用 癌变与雄激素非依赖性转化。Src和ETK作为 将探索治疗靶点。我们在过去资助期的成果有助于基本 神经内分泌分化和神经肽在雄激素非依赖性中的作用 前列腺癌的生长，Src激酶复合体参与雄激素的不适当激活 受体，以及ETK酪氨酸激酶在前列腺癌发生中的致癌作用。此外，通过我们的 合作伙伴，我们开发了体内前列腺癌小鼠模型和潜在的Src/ETK抑制剂 很复杂。然而，Src激酶复合体激活雄激素受体的详细机制和 目前，Src激酶复合体的抑制剂诱导细胞杀伤的机制仍不清楚。利用这一优势 在过去的赠款期间开发的发现和试剂，本提案旨在 更好地了解Src酪氨酸激酶复合体激活的机制 雄激素受体和保护前列腺癌细胞免于自噬和凋亡死亡。项目叙事 前列腺癌最令人不安的方面之一是它进化到雄激素非依赖性， 目前还没有有效的治疗方法。目前的建议直接涉及 这一进化的机制，并确定了参与这一过程的几个关键酪氨酸激酶。 进程。此外，这项提案将提供有关以下机制的重要信息 酪氨酸激酶抑制剂对细胞的杀伤作用并测试使用这些抑制剂的潜在益处 治疗前列腺癌。

ABSTRACT This proposal ¿ tyrosine kinases and prostate cancer¿ began in 1998 with the development of tyrosine kinase display approach and the first comprehensive tyrosine kinase profile of prostate cancer cells. In the ensuing years, tyrosine kinases involved in neuroendocrine differentiation and androgen independence were identified and the processes characterized. This led to the discovery of a complex of tyrosine kinases Src, Etk and FAK (referred to as Src kinase complex) as a central integrator of signals emanating from tyrosine kinase receptor, cytokine receptor and G-protein coupled receptor. These tyrosine kinases present novel targets for potential therapeutic intervention. The present proposal is focused on prostate cancer biology and etiology, especially the involvement of Src/Etk tyrosine kinase complex in prostate carcinogenesis and androgen independence conversion. The potential of Src and Etk to serve as therapeutic targets will be explored. Our results in the past grant period contributed to the basic understanding of the roles of neuroendocrine differentiation and neuropeptide in androgen independent growth of prostate cancers, the involvement of Src kinase complex in inappropriate activation of androgen receptor, and the oncogenic role of Etk tyrosine kinase in prostate carcinogenesis. In addition, with our collaborators, we developed in vivo prostate cancer mouse models and potential inhibitors for the Src/Etk complex. Yet, the detailed mechanisms whereby Src kinase complex activates androgen receptor and the inhibitors of Src kinase complex induce cell killing remain largely unknown. Taking advantage of the discoveries and the reagents developed in the past grant period, the present proposal is designed to provide a better understanding of the mechanisms whereby Src tyrosine kinase complex activates androgen receptor and protects prostate cancer cells from autophagic and apoptotic death. Project Narrative One of the most troubling aspects of prostate cancer is its evolution to androgen independence, to which no effective treatment has been developed. The present proposal deals directly with the mechanisms of this evolution and has identified several key tyrosine kinases involved in this process. In addition, this proposal will provide important information concerning the mechanisms of cell killing by tyrosine kinase inhibitors and test the potential benefits of using these inhibitors in treating prostate cancers.