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: 6785866
• 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/6785866
• 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）：肥大细胞瘤（MCT）是最常诊断出的狗的恶性肿瘤。我们之前已经证明，至少 30% 的犬 MCT 具有原癌基因 c-kit 突变，该突变由编码负调节近膜结构域的外显子 11/12 中的串联重复组成。这些突变导致 Kit 在没有配体结合的情况下发生组成型磷酸化。 Kit 的失调也被发现发生在许多人类肿瘤中，包括异常表达（小细胞肺癌、泌尿生殖系统癌症）和导致组成性激活的细胞质结构域突变（肥大细胞疾病、胃肠道间质瘤）。最近对各种实验性激酶抑制剂的研究表明，抑制 Kit 信号传导可能对患有这些恶性肿瘤的患者有显着的益处。然而，为了使其应用取得成功，更清楚地定义 c-kit 突变在肿瘤疾病发生和进展中的作用至关重要。该提议的假设是，c-kit 的激活突变通过促进细胞存活和诱导与侵袭和转移相关的金属蛋白酶基因表达，与恶性肥大细胞疾病的发生和进展相关。本研究的具体目的是：1）对狗 MCT 中的 c-kit 突变进行细致的表征，包括它们对 MCT 生物学行为的影响，并识别与其发展相关的潜在风险因素； 2) 通过产生在高度调控的诱导型启动子下表达各种形式的突变c-kit的转基因小鼠，研究Kit失调对体内正常细胞群的影响； 3) 在体外和 Kit 突变小鼠模型中评估二氢吲哚酮激酶抑制剂对失调 Kit 的影响。将小鼠 Kit 失调的详细研究与狗 c-kit 突变自发模型的综合研究相结合，将有助于阐明此类突变的生物学和生化后果。此外，将激酶抑制剂纳入这些研究提供了一个独特的机会来评估此类药物在治疗 Kit 功能障碍明显的肿瘤疾病中的潜在用途和功效。