Overcoming acquired resistance to EGFR inhibitors in lung cancer

克服肺癌对 EGFR 抑制剂的获得性耐药

• 批准号: 7255055
• 负责人: WILLIAM PAO
• 金额: $ 31.22万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7255055
• 关键词: Affect; Amino Acid Substitution; Amino Acids; Applications Grants; Award; Binding; Biochemical; Clinical; Data; Development; Disease Progression; Drug-sensitive; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exons; Funding; Gefitinib; Genetically Engineered Mouse; Gleevec; Goals; Grant; Human; Imatinib; Individual; Knowledge; Lung Adenocarcinoma; Malignant neoplasm of lung; Methionine; Molecular; Mus; Mutation; Patients; Pharmaceutical Preparations; Phosphotransferases; Progressive Disease; Property; Resistance; Specimen; Structure; Techniques; Tetracycline; Tetracyclines; Transgenes; Transgenic Animals; Tyrosine Kinase Domain; Tyrosine Kinase Inhibitor; bcr-abl Fusion Proteins; experience; improved; kinase inhibitor; mutant; neoplastic cell; response; tumor

DESCRIPTION (provided by applicant): Patients whose lung adenocarcinomas harbor specific mutations within the exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) frequently experience clinical and radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva). However, after about one year, these patients develop progression of disease. We and others have shown that in addition to primary drug-sensitive EGFR mutations, tumor cells from about half of patients with such "acquired resistance" contain a second mutation in the EGFR kinase domain. From crystal structure analyses, the resulting amino acid change (T790M) is predicted to block binding of drug to the ATP pocket via steric clash resulting from introduction of the bulky methionine residue. The T790M mutation is analogous to common secondary mutations in other kinases (e.g. BCR-ABL, T315I) found in patients with acquired resistance to another kinase inhibitor, imatinib (Gleevec). The overall goals of this revised proposal are to use human tumor specimens, genetically engineered mice, and various molecular and biochemical techniques to enhance knowledge about the subset of EGFR- mutant harboring lung adenocarcinomas that develop acquired resistance to gefitinib and erlotinib. An improved understanding of acquired resistance to these agents will hopefully allow us to both treat progressive disease and suppress the development of acquired resistance. Thus, we aim to: 1) Determine the mutational status of the EGFR kinase domain in tumor cells from patients with (up to 80 individuals) with acquired resistance to gefitinib or erlotinib, and establish how newly "acquired" mutations affect biochemical properties of EGFR, such as kinase activity and sensitivity to EGFR TKIs, and 2) Characterize transgenic animals carrying tetracycline-inducible transgenes that encode the common T790M resistance mutation by itself and in the context of a drug-sensitive EGFR mutation (the exon 21 amino acid substitution L858R or the exon 19 deletion L747-S752), comparing them to mice that express a drug-sensitive EGFR mutation alone.

描述（由申请人提供）：肺腺癌患者在编码表皮生长因子受体（EGFR）酪氨酸激酶结构域的外显子中存在特定突变，这些患者经常会对选择性 EGFR 酪氨酸激酶抑制剂（TKI）吉非替尼（吉非替尼）产生临床和放射学反应。易瑞沙（Iressa）或厄洛替尼（Tarceva）。然而，大约一年后，这些患者的疾病出现进展。我们和其他人已经证明，除了主要的药物敏感 EGFR 突变之外，来自大约一半具有这种“获得性耐药”的患者的肿瘤细胞在 EGFR 激酶结构域中含有第二种突变。根据晶体结构分析，预计由此产生的氨基酸变化 (T790M) 将通过引入庞大的蛋氨酸残基产生的空间冲突来阻止药物与 ATP 袋的结合。 T790M 突变类似于在对另一种激酶抑制剂伊马替尼（格列卫）获得耐药性的患者中发现的其他激酶（例如 BCR-ABL、T315I）中常见的二次突变。该修订提案的总体目标是利用人类肿瘤标本、基因工程小鼠以及各种分子和生化技术来增强对携带吉非替尼和厄洛替尼产生获得性耐药的肺腺癌的 EGFR 突变体子集的了解。更好地了解这些药物的获得性耐药性将有望使我们能够治疗进行性疾病并抑制获得性耐药性的发展。因此，我们的目标是：1) 确定对吉非替尼或厄洛替尼获得性耐药的患者（最多 80 名个体）的肿瘤细胞中 EGFR 激酶结构域的突变状态，并确定新的“获得性”突变如何影响 EGFR 的生化特性，例如激酶活性和对 EGFR TKI 的敏感性，以及 2) 表征携带四环素诱导转基因的转基因动物，这些转基因本身和环境中编码常见的 T790M 耐药突变药物敏感性 EGFR 突变（外显子 21 氨基酸取代 L858R 或外显子 19 缺失 L747-S752），将它们与仅表达药物敏感性 EGFR 突变的小鼠进行比较。