DDR2 kinase inhibition in squamous cell lung carcinomas

鳞状细胞肺癌中的 DDR2 激酶抑制

基本信息

批准号：
8237129
负责人：
MATTHEW L. MEYERSON
金额：
$ 42.66万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-11 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8237129
关键词：
2-tyrosine Advanced Development Animal Model Animal Structures Animals Biochemical Biological Assay Biological Models Cancer Model Cell Line Cell Proliferation Cell model Cells Cellular Assay Chemistry Chronic Myeloid Leukemia Clinical Trials Dasatinib Data Development Ectopic Expression Engineering Epidermal Growth Factor Receptor Epithelial Cells Epithelium FDA approved Foundations Gatekeeping Genes Genetic Goals Growth In Vitro Instruction Lead Letters Libraries Lung Malignant Epithelial Cell Malignant Squamous Cell Neoplasm Malignant neoplasm of lung Mediating Messenger RNA Modality Modeling Modification Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenic Open Reading Frames Pathogenesis Patients Phosphotransferases Protein Kinase Protein Tyrosine Kinase Proteins Relative (related person)Research Personnel Resistance Resistance development Resource Sharing Specificity Squamous Cell Squamous Cell Lung Carcinoma Squamous Epithelium Stem cells Structure Testing Transgenic Mice Tumor-Derived Tyrosine Kinase Inhibitor Work cancer cell cancer type discoidin domain receptor 2 in vitro testing inhibitor/antagonist killings kinase inhibitor knock-down lung basal segment mouse model mutant next generation novel novel therapeutics resistance allele resistance mechanism small molecule therapeutic target tumor

项目摘要

PROJECT SUMMARY (See instructions): In our Preliminary Studies, we found that DDR2, the discoidin domain receptor 2 tyrosine kinase gene, is somatically mutated in 3 to 4% of lung squamous cell carcinomas (lung SCC). Knock-down of DDR2 kills lung SCC cells bearing DDR2 mutations. Furthermore, treatment of DDR2-mutant lung SCC cells with the tyrosine kinase inhibitor dasatinib significantiy decreases cell proliferation; the effects of dasatinib are rescued by over-expression of DDR2 bearing the dasatinib-resistant T654M gatekeeper mutation. We now aim to develop DDR2 further as a therapeutic target for lung SCC. Our specific aims are to work with the other Projects and the shared resource Cores as follows: -Specific Aim 1. We will characterize the oncogenic potential of tumor-derived DDR2 mutants in the basal epithelium of the lung using cellular and animal model systems. We will work with Core C (Animal) to generate transgenic mouse models for lung basal epithelium-specific expression of DDR2 mutants and assay for tumor formation. We will also express DDR2 mutant mRNA in basal lung epithelium and test for oncogenic effects. These animal and cellular models will be used to assess the impact of disruption of DDR2 function both by genetic modification and by small molecule inhibitors. -Specific Aim 2. We will evaluate mechanisms of resistance to the DDR2 inhibitor, dasatinib, in squamous lung cancer models. To study c/s resistance to dasatinib, we will engineer and/or select for dasatinib resistance alleles in DDR2 and test their sensitivities to dasatinib and other kinase inhibitors. In addition, we will screen for trans resistance by ectopic expression of open reading frame libraries. -Specific Aim 3. Develop potent and selective inhibitors of DDR2 using biochemical and cellular assays, their effects. We will collaborate with Core A (Chemistry) and Core B (Structure) to optimize lead compounds identified by Core A as mutant-specific inhibitors of DDR2 with greater DDR2 kinase specificity relative to dasatinib. These optimized inhibitors will be tested in both lung SCC-derived cell lines and in the cellular and animal model systems developed in Aim 1, including models engineered to be resistant to dasatinib. Through these efforts, this project will advance the development of DDR2 inhibitors as potential treatments for squamous cell carcinomas of the lung.

项目摘要（请参阅说明）：在我们的初步研究中，我们发现DDR2（盘状蛋白受体2酪氨酸激酶基因）在3至4％的肺鳞状细胞癌（肺SCC）中被体形突变。 DDR2的敲除杀死带有DDR2突变的肺SCC细胞。此外，用DDR2突变的肺SCC细胞与酪氨酸激酶抑制剂dasatinib有效降低细胞增殖。达沙替尼的效果通过过度表达的DDR2携带，耐达沙替尼的T654M守门人突变。现在，我们的目标是进一步开发DDR2作为肺SCC的治疗靶点。我们的具体目的是与其他项目和共享资源核心合作，如下所示： - 特异性目标1。我们将使用细胞和动物模型系统来表征肺部基底上皮中肿瘤衍生的DDR2突变体的致癌潜力。我们将与Core C（动物）合作，生成用于DDR2突变体肺基底上皮特异性表达的转基因小鼠模型和肿瘤形成的测定。我们还将在基底肺上皮中表达DDR2突变体mRNA，并测试致癌作用。这些动物和细胞模型将用于评估通过遗传修饰和小分子抑制剂的DDR2功能破坏的影响。 - 特定目标2。我们将评估鳞状肺癌模型中对DDR2抑制剂dasatinib的抗性机制。为了研究对达沙替尼的C/S耐药性，我们将在DDR2中设计和/或选择达沙替尼的抗性等位基因，并测试其对达沙替尼和其他激酶抑制剂的敏感性。此外，我们将通过开放阅读框库的异位表达筛选跨性电阻。 - 特异性目标3。使用生化和细胞测定的DDR2的有效和选择性抑制剂，其作用。我们将与Core A（化学）和Core B（结构）合作，以优化由Core A鉴定为DDR2的突变特异性抑制剂，相对于Dasatinib，DDR2激酶特异性较大。这些优化的抑制剂将在肺SCC衍生的细胞系以及AIM 1中开发的细胞和动物模型系统中进行测试，其中包括设计为对达沙替尼具有抗性的模型。通过这些努力，该项目将推进DDR2抑制剂的发展，作为对肺部鳞状细胞癌的潜在疗法。