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: 7615548
• 负责人: JEFFREY E SETTLEMAN
• 金额: $ 64.31万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615548
• 关键词: Address; Affect; Biochemical; Biological; Biological Assay; Cancer Patient; Cancer cell line; Candidate Disease Gene; Cell Culture Techniques; Cells; Cellular Assay; Clinical; Complex; Dependence; Drug Hypersensitivity; Drug-sensitive; EGF gene; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; ErbB Receptor Family Protein; Exhibits; Family member; Gefitinib; Gene Expression Profile; Gene Expression Profiling; Human; Hypersensitivity; In Vitro; Ligands; Link; Lung; Lung Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Property; Proteins; Research Personnel; Role; Signal Transduction; Site; Somatic Mutation; Substrate Specificity; Testing; Tumor-Derived; addiction; base; drug mechanism; drug sensitivity; enzyme activity; experience; insight; killings; lung tumorigenesis; mutant; neoplastic cell; novel; programs; receptor; response; synthetic peptide; tumor; tumorigenesis

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（由申请人提供）：〜10％的非小细胞肺癌患者对吉非替尼（IRESSA）（表皮生长因子受体的选择性抑制剂（EGFR））的反应很大，并且肿瘤中体细胞EGFR突变的存在准确地预测临床反应。突变EGFR表现出EGF诱导的信号传导的定性改变，这表明突变体EGFR的明显信号在某些肺肿瘤中有助于药物反应性。 在这里，将建立这些EGFR突变的致癌机制以及吉非替尼敏感性的基础机制。还将检查在缺乏EGFR突变的一小部分患者中看到的药物反应的分子基础。提出了四个具体目的：1：建立生化机制，通过该机制，EGFR突变体有助于肺部肿瘤。这将涉及通过纯化的激酶和合成肽底物的体外酶研究来阐明突变EGFR的生化区别。将比较野生型和几种肿瘤衍生的EGFR突变体的酶活性，底物特异性和信号传导复合物。细胞培养分析将用于将突变体EGFR的信号传导特性与对EGF的不同生物学反应联系起来。 2：确定具有EGFR突变体的肿瘤中药物敏感性和EGFR依赖性的基础。酶和细胞测定法将用于比较对野生型和突变EGFR的药物影响。 “癌基因成瘾”假设将在突变体EGFR的信号传导模型中检查。 3：检查其他ERBB受体在突变EGFR的致癌功能和药物敏感性中的作用。该假设将检验，突变体EGFR和另一个ERBB受体的异二聚体有助于突变EGFR和/或药物敏感性的致癌作用。 4：在没有EGFR突变的情况下确定吉非替尼反应的分子基础。将在缺乏EGFR突变的药物反应性肿瘤中寻找突变的搜索。为了建立基于细胞的设置以研究反应机制，将筛选肺癌细胞系以鉴定缺乏EGFR突变的药物敏感线。最后，将使用基于微阵列的基因表达分析来确定定义药物反应性的基因表达特征。总之，这些研究有望提供对这一新型EGFR突变体的致癌活性的分子机制的重要见解，以及含有这些突变的肿瘤表现出的药物超敏反应。

项目成果

Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non-small cell lung cancer following cisplatin exposure: a cell culture model of second-line erlotinib treatment.

• DOI: 10.1158/1078-0432.ccr-08-0093
• 发表时间: 2008-11-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Chin TM;Quinlan MP;Singh A;Sequist LV;Lynch TJ;Haber DA;Sharma SV;Settleman J
• 通讯作者: Settleman J