EGFR Mutations in non-Small Cell Lung Cancer

描述（由申请人提供）：非小细胞肺癌约占肺癌的85%，现有治疗晚期疾病患者的疗效甚微。已经开发了针对表皮生长因子受体（EGFR）的药剂。然而，只有10-20%的复发性非小细胞肺癌患者对常见的EGFR抑制剂吉非替尼和厄洛替尼治疗有部分或完全反应。EGFR的点突变和缺失与几乎所有患者对吉非替尼的临床应答相关。具有EGFR突变的肿瘤细胞系也对体外吉非替尼治疗敏感。该提案旨在进一步表征非小细胞肺癌受试者的肿瘤和肿瘤细胞系中EGFR的突变。目的1将是确定在以前未经治疗的晚期非小细胞肺癌患者中表皮生长因子受体突变的频率和类型，这些患者前瞻性地进入使用表皮生长因子受体抑制剂的试验。我们有两组135例晚期非小细胞肺癌患者，他们将接受研究。这些队列将包括对治疗有反应的患者、病情稳定的患者和进行性非小细胞肺癌患者。目的2是确定表皮生长因子受体酪氨酸激酶治疗的非小细胞肺癌患者中表皮生长因子受体突变、治疗反应、进展时间和生存率之间的关系。这样做是为了确定特定的突变是否会导致不同的患者结局，包括缓解、缓解持续时间和生存期。我们已经组建了一个研究者联盟，他们研究了给予单药EGFR抑制剂的未经治疗的非小细胞肺癌患者，使我们能够组建多个具有缓解和EGFR突变的大型患者组。目的3将研究EGFR抑制剂治疗前后非小细胞肺癌患者的肿瘤和肿瘤细胞系，以确定遗传变化与表皮生长因子受体抑制剂敏感性和耐药性之间的关系。NCI-H3255和DFCI-LU- 011是具有EGFR突变的腺癌细胞系。将研究它们对EGFR抑制剂的敏感性、下游信号传导事件以及与具有野生型EGFR的细胞系相比的细胞死亡机制。这些研究将为EGFR抑制剂的未来试验提供指导。

DESCRIPTION (provided by applicant): Non-small cell lung carcinoma is responsible for approximately 85% of lung cancer and existing treatments for patients with advanced disease remain only marginally effective. Agents directed against the epidermal growth factor receptor have been developed (EGFR). However, only 10-20% of patients with relapsed non-small cell lung cancer have a partial or complete response to treatment with the common EGFR inhibitors, gefitinib and erlotinib. Point mutations and deletions in EGFR are associated with clinical responses to gefitinib in nearly all patients. Tumor cell lines with EGFR mutations are also sensitive to gefitinib treatment in vitro. This proposal is to further characterize the mutations in the EGFR in the tumors and tumor cell lines from subjects with non-small cell lung cancer. Aim 1 will be to establish the frequency and type of mutations in the epidermal growth factor receptor in previously untreated patients with advanced non-small cell lung cancer prospectively entered into trials using epidermal growth factor receptor inhibitors. We have two patient cohorts of 135 patients with advanced non-small cell lung cancer who are going to be studied. These cohorts will include those who respond to treatment, patients with stable disease, and patients with progressive non-small cell lung cancer. Aim 2 is to determine the relationship between epidermal growth factor receptor mutations, response to treatment, time to progression, and survival in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase. This will be done to determine if specific mutations give rise to different patient outcomes that include response, duration of response, and survival. We have assembled a consortium of investigators that have studied untreated patients with non-small cell lung cancer given single agent EGFR inhibitors to enable us to assemble multiple large groups of patients with responses and EGFR mutations. Aim 3 will be to study the tumors and tumor cell lines from patients with non-small cell lung cancer before and after treatment with EGFR inhibitors to determine the relationship between genetic changes and sensitivity and resistance to epidermal growth factor receptor inhibitors. NCI-H3255 and DFCI-LU- 011 are adenocarcinoma cell lines with EGFR mutations. Their sensitivity to EGFR inhibitors, downstream signaling events, and the mechanism of cell death compared to cell lines with wild type EGFR will be studied. These studies will provide guidance for future trials of EGFR inhibitors.