Gefitinib-sensitive EGF receptor mutants in lung cancer

肺癌中吉非替尼敏感的 EGF 受体突变体

• 批准号: 6957232
• 负责人: JEFFREY E SETTLEMAN
• 金额: $ 55.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6957232
• 关键词: antineoplastics; biological signal transduction; cell line; enzyme activity; epidermal growth factor; gene expression; gene expression profiling; gene mutation; growth factor receptors; human tissue; kinase inhibitor; microarray technology; molecular oncology; neoplasm /cancer genetics; neoplasm /cancer pharmacology; nonsmall cell lung cancer; protein tyrosine kinase; synthetic peptide

DESCRIPTION (provided by applicant): ~10% of non-small cell lung cancer patients respond dramatically to Gefitinib (Iressa), a selective inhibitor of epidermal growth factor receptor (EGFR), and the presence of somatic EGFR mutations in tumors accurately predicts a clinical response. Mutant EGFRs exhibit a qualitative alteration of EGF-induced signaling suggesting that distinct signaling by mutant EGFRs contributes to drug-responsiveness in some lung tumors. Here, the oncogenic mechanism of these EGFR mutations and the mechanism underlying gefitinib-sensitivity will be established. The molecular basis for drug-response seen in a small subset of patients with tumors lacking EGFR mutations will also be examined. Four Specific Aims are proposed: 1: To establish the biochemical mechanism by which EGFR mutants contribute to lung tumors. This will involve elucidating biochemical distinctions of mutant EGFRs through in vitro enzyme studies with purified kinase and synthetic peptide substrates. Enzyme activity, substrate specificity, and signaling complexes will be compared for wild-type and several tumor-derived EGFR mutants. A cell culture assay will be used to link the altered signaling properties of mutant EGFRs to distinct biological responses to EGF. 2: To determine the basis for drug-sensitivity and EGFR-dependence in tumors harboring EGFR mutants. Enzyme and cellular assays will be used to compare drug effects on wild-type and mutant EGFRs. The "oncogene addiction" hypothesis will be examined in a cell culture model of signaling by mutant EGFRs. 3: To examine the role of other ErbB receptors in the oncogenic function and drug sensitivity of mutant EGFR. The hypothesis will be tested that heterodimers of mutant EGFR and another ErbB receptor contribute to the oncogenic actions of mutant EGFR and/or drug sensitivity. 4: To determine the molecular basis for gefitinib-response in the absence of EGFR mutations. A search for mutations in candidate genes in drug responsive tumors lacking EGFR mutations will be conducted. To establish a cell-based setting to study the response mechanism, lung cancer cell lines will be screened to identify drug-sensitive lines lacking EGFR mutations. Finally, microarray-based gene expression profiling will be used to identify a gene expression signature that defines drug-responsiveness. Together, these studies are expected to provide important insights into the molecular mechanisms that underlie the oncogenic activity of this novel class of EGFR mutants and the drug hypersensitivity exhibited by tumors that harbor these mutations.

描述（由申请方提供）：约10%的非小细胞肺癌患者对吉非替尼（易瑞沙）（一种表皮生长因子受体（EGFR）的选择性抑制剂）有显著反应，肿瘤中存在体细胞EGFR突变可准确预测临床反应。突变EGFR表现出EGF诱导的信号转导的定性改变，表明突变EGFR的不同信号转导有助于某些肺肿瘤的药物反应性。 在这里，这些EGFR突变的致癌机制和吉非替尼敏感性的潜在机制将被建立。还将检查在一小部分缺乏EGFR突变的肿瘤患者中观察到的药物应答的分子基础。本研究的目的有四：1：建立EGFR突变体致肺癌的生物化学机制。这将涉及通过使用纯化的激酶和合成肽底物进行体外酶研究来阐明突变型EGFR的生化差异。酶活性，底物特异性，和信号复合物将野生型和几个肿瘤衍生的EGFR突变体进行比较。细胞培养试验将用于将突变EGFR的改变的信号传导特性与对EGF的不同生物学反应联系起来。2：确定携带EGFR突变体的肿瘤的药物敏感性和EGFR依赖性的基础。酶和细胞测定将用于比较药物对野生型和突变型EGFR的作用。“癌基因成瘾”假说将在突变EGFR信号传导的细胞培养模型中进行检验。3：研究其他ErbB受体在突变型EGFR的致癌功能和药物敏感性中的作用。将检验突变型EGFR和另一种ErbB受体的异二聚体有助于突变型EGFR的致癌作用和/或药物敏感性的假设。4：确定无EGFR突变情况下吉非替尼反应的分子基础。将在缺乏EGFR突变的药物应答肿瘤中进行候选基因突变的检索。为了建立基于细胞的环境来研究反应机制，将筛选肺癌细胞系以鉴定缺乏EGFR突变的药物敏感性细胞系。最后，基于微阵列的基因表达谱将用于确定定义药物反应性的基因表达特征。总之，这些研究有望为这类新型EGFR突变体的致癌活性以及携带这些突变的肿瘤所表现出的药物超敏反应的分子机制提供重要见解。