Sphingosine-1-phosphate receptor subtype 3 in oncogenic K-Ras mutant-driven lung adenocarcinoma

目的：K-RAS是一种正常的细胞蛋白。致癌K-RAS突变，导致急性加重期 K-RAS蛋白的激活，导致肿瘤的发生和发展。在超过25%的患者中发现K-RAS突变 人类非小细胞肺癌(NSCLC)。然而，由K-RAS突变引起的肺癌是 对化疗和靶向药物一般都是无效的。此外，对毒品的识别 在治疗上抑制K-RAS是不成功的，这表明还需要其他方法。 鞘氨醇-1-磷酸(S1P)是人体内存在的一种重要的脂质介质。S1P受体水平 亚型3(S1PR3，一种结合S1P并介导S1P功能的受体)在肺癌中增加。 S1PR3调节多种致癌功能，这些功能对人类肺的进展至关重要 腺癌(LADC)。抑制S1PR3可显著减少动物肺癌的生长。 此外，癌基因K-RAS突变体在体外和体内都能刺激S1PR3的表达。总体而言， 本申请的目的是表征S1PR3在K-RAS突变驱动的LADC中的关键作用，并 研究抑制S1PR3是否为K-RAS突变驱动的人LADC提供了有效的治疗方法。 假设、具体目标和研究设计：本建议的假设是“加剧的S1PR3” 活性有助于致癌的K-RAS突变驱动的LADC进展，至少部分是通过促进 巨噬细胞渗入LADC。S1PR3是治疗K-RAS的潜在靶点 变种人驱动的LADC。为了检验这一假设，本文提出了两个目标。目标1.一种转基因小鼠 表达突变K-Ras蛋白且缺乏S1PR3的小鼠将被用来确定其关键作用 S1PR3在K-RAS突变体驱动的LADC中的表达。此外，S1PR3在募集炎性巨噬细胞中的作用 将对LADC进行调查。目的2.高选择性的S1PR3拮抗剂TY-52156将用于展示 S1PR3抑制是对致癌K-RAS突变驱动的LADC的有效干预的概念验证。 该项目的健康相关性：肺癌仍然是癌症相关死亡的主要原因。主 本申请的目的是表征S1PR3在K-RAS突变驱动的LADC进展中的关键作用。 这项申请的成功完成有望为这场战斗提供多个干预点 针对致癌的K-RAS突变驱动的LADC。

Objectives: K-Ras is a normal cellular protein. Oncogenic K-Ras mutation, leading to the exacerbated activation of K-Ras protein, causes tumor initiation and progression. K-Ras mutation is found in more than 25% of human non-small cell lung carcinomas (NSCLC). However, lung cancers caused by K-Ras mutation are generally refractory to chemotherapy as well as targeted agents. Moreover, the identification of drugs to therapeutically inhibit K-Ras has been unsuccessful, suggesting that other approaches are required. Sphingosine-1-phosphate (S1P) is an important lipid mediator present in our body. Levels of S1P receptor subtype 3 (S1PR3, a receptor which binds S1P and mediates S1P functions) are increased in lung carcinomas. S1PR3 regulates various tumorigenic functions which are critical for the progression of human lung adenocarcinoma (LADC). Inhibition of S1PR3 profoundly diminishes lung carcinoma growth in animals. Furthermore, oncogenic K-Ras mutant stimulates S1PR3 expression in vitro and in vivo. Collectively, the objectives of this application is to characterize the critical role of S1PR3 in K-Ras mutant-driven LADC, and to investigate whether S1PR3 inhibition provides an effective therapy for K-Ras mutant-driven human LADC. Hypothesis, Specific aims, and Study designs: The hypothesis of this proposal is “Exacerbated S1PR3 activity contributes to oncogenic K-Ras mutant-driven LADC progression, at least in part, by promoting macrophage infiltration to LADC. S1PR3 represents a potential therapeutic target for the treatment of K-Ras mutant-driven LADC.” Two aims are proposed to test this hypothesis. Aim 1. A genetically engineered mouse strain, mice expressing mutated K-Ras protein and lacking S1PR3, will be utilized to determine the critical role of S1PR3 in K-Ras mutant-driven LADC. In addition, the role of S1PR3 in recruiting inflammatory macrophages to LADC will be investigated. Aim 2. TY-52156, a highly selective S1PR3 antagonist, will be used to demonstrate the proof-of-concept that S1PR3 inhibition is an effective intervention for oncogenic K-Ras mutant-driven LADC. Health relatedness of the project: Lung cancer remains the leading cause of cancer-related deaths. The main goal of this application is to characterize the critical role of S1PR3 in K-Ras mutant-driven LADC progression. The successful completion of this application is expected to provide multiple intervention points for the fight against oncogenic K-Ras mutant-driven LADC in the future.