Determinants of Resistance to Erlotinib in NSCLC

表皮生长因子信号转导通路在维持血管生成中起着重要作用。 某些上皮性恶性肿瘤的生长和存活，包括非小细胞肺癌(NSCLC)。 埃洛替尼(Tarceva，OSI-774)是一种表皮生长因子受体(EGFR)酪氨酸的选择性抑制剂 在一项随机的III期临床研究中，该激酶已显示出延长了患者的生存时间 难治性非小细胞肺癌和非常耐受的毒性特征。使用厄洛替尼的结果可以显著改善，如果 根据肿瘤分子的敏感性和/或决定因素，可以成功地选择患者 对这种毒剂的抵抗力。这项提案的主要目标是确定以下决定因素 新切除的非小细胞肺癌裸鼠移植瘤对厄洛替尼的敏感性/耐药性 临床相关的非小细胞肺癌模型。正在测试的广泛假设是对厄洛替尼的敏感性需要 肿瘤的生长和/或存活依赖于EGFR轴，并且对厄洛替尼的耐药性是 由可选的信号转导通路激活引起。具体目标是：1.发展一种 人非小细胞肺癌裸鼠异种移植瘤文库的构建及遗传程度的评估 异种移植与患者原发肿瘤切除的相似性。2.确定 厄洛替尼在非小细胞肺癌异种移植中的抗肿瘤活性研究 反应、稳定疾病和肿瘤进展，并开发一种数学算法，包括临床 和分子参数计算艾洛替尼治疗后肿瘤反应/进展的概率 个体患者和，3.确认算法在一组患者中的预测价值 化疗耐药非小细胞肺癌因其获得应答或病情稳定的可能性较高而被选中 单药厄洛替尼治疗。

The epidermal growth factor signal transduction pathway plays an important role in sustaining the growth and survival of certain epithelial malignancies, including non-small cell lung cancer (NSCLC). Erlotinib (Tarceva, OSI-774) is a selective inhibitor of the epidermal growth factor receptor (EGFR)tyrosine kinase that has shown prolongation of survival in a randomized Phase III clinical study in patients with refractory NSCLC and a very tolerable toxicity profile. Results with erlotinib could be markedly improved if patients could be successfully selected based on their tumor molecular determinants of sensitivity and/or resistance to this agent. The main objective of this proposal is to identify the determinants of sensitivity/resistance to erlotinib in freshly resected NSCLC tumors heterotransplanted in nude mice as clinically relevant models of NSCLC. The broad hypothesis being tested is that sensitivityto erlotinib requires a dependence of the tumor for growth and/or survival on the EGFR axis and that resistance to erlotinib is caused by activation of alternative signal transduction pathways. The specific aims are:1. To develop a library of human NSCLC tumors heterotransplanted in nude mice and to assess the degree of genetic similarity between the heterotransplants and the primary tumors resected from the patients. 2. To determine the antitumor activity of erlotinib in NSCLC heterotransplants, to identify molecular determinants of tumor response, stable disease, and tumor progression, and to develop a mathematical algorithm including clinical and molecular parameters to calculate the probability of tumor response/progression with erlotinib therapy in individual patients and,3. To confirm the predictive value of the algorithm in a group of patients with chemoresistant NSCLC selected for their high probability of achieving a response or stable disease with single agent erlotinib therapy.