EGFRvIII Mutation in Tumorigenesis and Sensitivity to Tyrosine Kinase Inhibitors

描述(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。虽然已经检测到不同类型的EGFR基因改变，但在人类癌症中，最常见的获得性EGFR基因改变似乎是细胞外域的部分缺失。在这些被截断的受体中，最常见的是激活变异体III EGFR缺失突变体(EGFRv11)。然而，由于EGFR基因位点的复杂结构，从基因组上证实EGFRv11在肺癌和其他类型的癌症中的存在是困难的。此外，EGFRv11在肺癌发病机制中的作用尚不清楚。我们实验室最近建立了EGFRv11在人肺鳞状细胞癌中的普遍流行，并通过可诱导的双基因小鼠模型证明了EGFRv11在肺中的致癌潜力。此外，我们还发现转化的EGFRv11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一个独特的机会来探索EGFRv11突变破坏细胞生长的机制，阐明EGFRv11与其他肺癌相关抑癌基因的缺失之间的遗传相互作用，并测试治疗EGFRv11的新疗法。我们假设，同时存在PTEN、P53或lnk4a/ARF缺失的肺EGFRv11肿瘤将更具侵袭性，对EGFR抑制剂的治疗更具抵抗力。我们还假设，慢性EGFR抑制剂治疗肺癌或携带EGFRv11的转化细胞可能通过获得EGFR基因的新突变而导致获得性耐药性的发展。最后，我们认为EGFRv11在其他类型的癌症中也很常见。通过成功实现我们的特定目标来检验这些假设，将促进我们对EGFRv11突变在肿瘤发生中的作用的理解，并为开发有效的治疗方法来治疗不同类型的癌症提供新的见解。

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.