EGFRvIII Mutation in Tumorigenesis and Sensitivity to Tyrosine Kinase Inhibitors

肿瘤发生中的 EGFRvIII 突变和对酪氨酸激酶抑制剂的敏感性

• 批准号: 7428779
• 负责人: Kwok Kin Wong
• 金额: $ 27.76万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-31 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7428779
• 关键词: Antibodies; Biochemical; Biological Models; Cancer Patient; Carcinoma; Cells; Chronic; Class; Complex; DNA; Development; EGFR Gene Amplification; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Extracellular Domain; Gefitinib; Genetic; Genomics; HKI272; Histocompatibility Testing; Human; In Vitro; Knockout Mice; Laboratories; Lead; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mutation; Oncogenic; Organ; PTEN gene; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Play; Prevalence; Protein p53; Receptor Protein-Tyrosine Kinases; Relapse; Resistance; Resistance development; Role; Screening procedure; Sensitivity and Specificity; Signal Pathway; Site; Squamous Cell Lung Carcinoma; Structure; Systems Analysis; TP53 gene; Testing; Therapeutic; Thinking; Transgenic Organisms; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Ursidae Family; Variant; antitumor drug; base; c-erbB-1 Proto-Oncogenes; cancer cell; cancer type; cell growth; cell transformation; epidermal growth factor receptor VIII; in vivo; insight; mouse model; mutant; neoplastic cell; novel; novel therapeutics; receptor; research study; resistance mechanism; response; small molecule; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor which plays an integral part in signaling pathways that control normal and malignant cell growth. Although diverse types of EGFR genetic alterations have been detected, the most common acquired genetic alterations of EGFR in human cancers appear to be partial deletions of the extracellular domain. The most common of these truncated receptors is the activating variant III EGFR deletion mutant (EGFRvlll). However, due to the complex structure of the EGFR gene locus, genomic confirmation of EGFRvlll existence in lung and other types of cancer has been difficult. Furthermore, the role of EGFRvlll in the pathogenesis of lung cancer is not known. Our laboratory has recently established the common prevalence of EGFRvlll in human lung squamous cell carcinoma and demonstrated the oncogenic potential of EGFRvlll in the lung through an inducible bitransgenic mouse model. Furthermore, we showed that EGFRvlll transformed cells and tumors are sensitive to irreversible small molecule EGFR inhibitors. Our established model systems offer a unique opportunity to explore the mechanisms by which EGFRvlll mutations deregulate cell growth, to elucidate the genetic interaction between EGFRvlll and the loss of other lung cancer relevant tumor suppressor genes, and to test novel therapeutics for the treatment of EGFRvlll bearing tumors. We hypothesize that lung EGFRvlll bearing tumors with concurrent PTEN, p53 or lnk4a/ARF loss will be more aggressive and be more resistant to EGFR inhibitor treatment. We also hypothesize that chronic EGFR inhibitor treatment of lung tumors or transformed cells bearing EGFRvlll might lead to the development of acquired resistance through the acquisition of new mutations in the EGFR gene. Lastly, we believe that the EGFRvlll is common in other cancer types. Testing of these hypotheses through successful implementation of our specific aims will advance our understanding of the role of the EGFRvlll mutation in tumorigenesis and provide new insights into the development of effective therapeutics for the treatment of different types of cancers that bear EGFRvlll.

描述（由申请人提供）：表皮生长因子受体（EGFR）是一种酪氨酸激酶受体，在控制正常和恶性细胞生长的信号通路中起着不可或缺的作用。尽管已检测到多种类型的EGFR遗传改变，但人类癌症中EGFR最常见的获得性遗传改变似乎是细胞外结构域的部分缺失。这些截短的受体中最常见的是活化变体III EGFR缺失突变体（EGFRvIII）。然而，由于EGFR基因座的复杂结构，在肺癌和其他类型的癌症中EGFR vIII存在的基因组确认一直是困难的。此外，EGFRvIII在肺癌发病机制中的作用尚不清楚。我们的实验室最近已经确定了EGFRvIII在人肺鳞状细胞癌中的常见患病率，并通过诱导型双转基因小鼠模型证明了EGFRvIII在肺中的致癌潜力。此外，我们表明EGFRvIII转化的细胞和肿瘤对不可逆的小分子EGFR抑制剂敏感。我们建立的模型系统提供了独特的机会来探索EGFRvIII突变解除细胞生长调节的机制，阐明EGFRvIII与其他肺癌相关肿瘤抑制基因的丢失之间的遗传相互作用，并测试用于治疗携带EGFRvIII的肿瘤的新疗法。我们假设具有同时发生的PTEN、p53或Ink 4a/ARF损失的携带EGFR vIII的肺肿瘤将更具侵袭性并且对EGFR抑制剂治疗更具抗性。我们还假设，肺肿瘤或携带EGFRvIII的转化细胞的慢性EGFR抑制剂治疗可能通过获得EGFR基因中的新突变而导致获得性抗性的发展。最后，我们相信EGFRvIII在其他癌症类型中是常见的。通过成功实现我们的特定目标来测试这些假设将促进我们对EGFRvIII突变在肿瘤发生中的作用的理解，并为开发用于治疗携带EGFRvIII的不同类型癌症的有效治疗剂提供新的见解。