Inhibitor-sensitive and -resistant EGFR mutants from lung cancer and glioblastoma

描述(申请人提供)：使用激酶抑制剂Gefitinib(易瑞沙)和erlotinib(Tarceva)治疗肺癌的患者显示出令人振奋的结果，肺癌是美国癌症死亡的主要原因。表皮生长因子受体酪氨酸激酶基因EGFR的激活突变在肺腺癌中频繁发生，并与对这些激酶抑制剂的反应有关。在过去的一年里，我们和其他人在人类肿瘤中发现了几种新的EGFR突变类型，如“初步数据”部分所述。1)次级激酶域突变，T790M，在激活的、抑制物敏感的EGFR突变的背景下，使人对吉非替尼和厄洛替尼产生耐药性。2)一类肺癌来源的激活EGFR突变，插入在外显子20中，对厄洛替尼和吉非替尼耐药。3)胶质母细胞瘤中存在EGFR胞外区的体细胞突变。我现在建议进行进一步的研究，以探索EGFR依赖的转化机制，以及肿瘤来源的EGFR突变对EGFR抑制剂的抵抗机制。这项工作的长期目标是改进肺腺癌、胶质母细胞瘤和其他依赖EGFR的肿瘤的治疗。具体地说，我提出了以下目标，与最近发现的EGFR突变体类别有关。具体目的1.针对一组转化的EGFR突变，检测特异性小分子EGFR抑制剂对EGFR依赖的细胞生长的抑制作用。具体目的2.分析EGFR依赖转化的结构和生化决定因素。具体目标3.确定激活的EGFR中导致对吉非替尼等EGFR抑制剂产生耐药性的继发性突变。具体目的4.确定肿瘤来源的EGFR胞外区的点突变是否正在转化，以及这些突变是否可以被小分子激酶抑制剂抑制。

DESCRIPTION (provided by applicant): Treatment with the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) has shown promising results for patients with lung cancer, the leading cause of cancer death in the United States. Activating mutations in the epidermal growth factor receptor tyrosine kinase gene, EGFR, occur frequently in lung adenocarcinoma and are associated with response to these kinase inhibitors. During the past year, we and others have identified several new classes of EGFR mutation in human tumors, as described in the "Preliminary Data" section. 1) A secondary kinase domain mutation, T790M, confers resistance to gefitinib and erlotinib in the setting of an activating, inhibitor-sensitive EGFR mutation. 2) One class of lung-cancer derived activating EGFR mutations, insertions within exon 20, are resistant to erlotinib and gefitinib. 3) Somatic mutations of the EGFR extracellular domain are found in glioblastoma. I now propose to conduct further studies to explore the mechanism of EGFR-dependent transformation and the mechanisms for resistance to EGFR inhibitors for tumor-derived EGFR mutations. The long-term goal of this work is to improve treatment of lung adenocarcinoma, glioblastoma, and other EGFR-dependent tumors. Specifically, I propose the following aims, tied to the recently discovered classes of EGFR mutants. Specific Aim 1. Test the inhibition of EGFR-dependent cell growth by specific small molecule EGFR inhibitors for a panel of transforming EGFR mutations. Specific Aim 2. Analyze the structural and biochemical determinants of EGFR-dependent transformation. Specific Aim 3. Identify secondary mutations in activated EGFR that cause resistance to EGFR inhibitors such as gefitinib. Specific Aim 4. Determine whether cancer-derived point mutations in the extracellular domain of EGFR are transforming and whether these mutants can be inhibited by small molecule kinase inhibitors.