c-Kit Mutations and Their Role in Tumor Biology

c-Kit 突变及其在肿瘤生物学中的作用

• 批准号: 6546067
• 负责人: Cheryl A London
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-02 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6546067
• 关键词: animal tissue; biological signal transduction; cancer registry /resource; cell population study; enzyme inhibitors; gene induction /repression; gene mutation; genetically modified animals; laboratory mouse; mast cell neoplasm; metalloendopeptidases; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; protein tyrosine kinase; protooncogene

DESCRIPTION (provided by applicant): Mast cell tumors (MCTs) are the most frequently diagnosed malignant tumor of the dog. We have previously demonstrated that at least 30% of canine MCTs possess mutations in the proto-oncogene c-kit consisting of tandem duplications in exons 11/12 encoding the negative regulatory juxtamembrane domain. These mutations result in constitutive phosphorylation of Kit in the absence of ligand binding. Dysregulation of Kit has also been found to occur in many human tumors including aberrant expression (small cell lung carcinoma, genitourinary cancers) and mutation in the cytoplasmic domain leading to constitutive activation (mast cell disorders, gastrointestinal stromal tumors). Recent studies with various experimental kinase inhibitors suggest that inhibition of Kit signaling may be of significant benefit to patients with these malignancies. However, for their application to be successful, it is critical that the role of c-kit mutations in the initiation and progression of neoplastic disorders be more clearly defined. The hypothesis underlying this proposal is that activating mutations of c-kit are associated with the development and progression of malignant mast cell disease through the promotion of cell survival and induction of metalloproteinase gene expression linked to invasion and metastasis. The specific aims of this study are: 1) to undertake a meticulous characterization of c-kit mutations in dog MCTs including their impact on the biologic behavior of MCTs, and identification of potential risk factors associated with their development; 2) to study the effect of Kit dysregulation on normal cell populations in vivo through the generation of transgenic mice expressing various forms of mutant c-kit under a highly regulated inducible promoter; and 3) to evaluate the effects of indolinone kinase inhibitors on dysregulated Kit both in vitro and in mouse models of Kit mutation. The integration of detailed investigations of Kit dysregulation in the mouse with comprehensive studies of a spontaneous model of c-kit mutation in the dog will help to clarify the biological and biochemical consequences of such mutations. Moreover, the incorporation of kinase inhibitors into these studies offers a unique opportunity to evaluate the potential usefulness and efficacy of such agents in the treatment of neoplastic diseases in which Kit dysfunction is evident.

描述（由申请人提供）：肥大细胞肿瘤（MCT）是狗最常见的恶性肿瘤。我们先前已经证明，在原始癌基因C-KIT中至少有30％的犬MCT具有突变，由外显子中的串联复制组成11/12编码负调控近膜结构域的串联重复。这些突变导致在没有配体结合的情况下，试剂盒的组成型磷酸化。在许多人类肿瘤中还发现了试剂盒的失调，包括异常表达（小细胞肺癌，泌尿生殖率癌）和细胞质结构域突变，导致本构激活（肥大细胞疾病，胃肠道遗传骨间质肿瘤）。对各种实验激酶抑制剂的最新研究表明，抑制套件信号传导对这些恶性肿瘤患者可能有很大的好处。但是，为了确保其应用成功，至关重要的是，更清楚地定义了C-KIT突变在肿瘤疾病的启动和进展中的作用。该提议的基本假设是，C-KIT的激活突变与通过促进细胞存活以及与浸润和转移有关的金属蛋白酶基因表达的诱导而与恶性肥大细胞疾病的发展和进展有关。这项研究的具体目的是：1）对狗MCT中C-KIT突变进行细致的表征，包括它们对MCT的生物行为的影响，并确定与其发育相关的潜在风险因素； 2）研究试剂盒失调对体内正常细胞群体的影响，通过在高度调节的可诱导型启动子下表达各种形式的突变c-kit的转基因小鼠； 3）评估吲哚酮激酶抑制剂对试剂盒突变模型中的试剂盒失调的影响。对小鼠的详细研究的详细研究整合了对狗自发的C-KIT突变模型的全面研究，将有助于阐明此类突变的生物学和生化后果。此外，将激酶抑制剂掺入这些研究中，为评估这种药物在治疗KIT功能障碍的肿瘤疾病中的潜在有用性和功效提供了独特的机会。