Mechanisms and Modulators of Sensitivity and Resistance to EGFR Inhibitors in Lu

EGFR突变型肺癌是肺癌的一个亚类，具有独特的生物学和临床特征。超过70% 肺癌患者在编码酪氨酸激酶的外显子中存在特定突变 EGFR的结构域经历了选择性EGFR酪氨酸激酶抑制剂(TKI)的放射反应， 吉非替尼(Iressa)或埃里奥替尼(Tarceva)，总体中位生存期约为30个月。然而，没有 病人被治愈了。大约一年后，就会产生获得性抵抗力。在以前的工作中，我们在 除了对原发药物敏感的EGFR突变外，超过一半的此类患者的肿瘤细胞 “获得性耐药”在EGFR激酶结构域中包含一个经常性的第二位点突变(T790M)。我们 用小鼠肺癌模型也证明了T790M介导的耐药性是可以克服的 通过第二代EGFR TKI，afatinib(BIBW2992)和抗EGFR的新组合 抗体，西妥昔单抗。根据我们的数据，这种组合在人体上的IB期临床试验现在已经完成 在这一患者队列中表现出前所未有的活跃，95%的临床受益率和35%的确诊 放射学应答率。临床发现激发了新的和关键的生物学问题 地址。在这里，基于有希望的新的初步数据，我们的目标是1)阐明HER2在 介导携带EGFR基因突变的T790M肺癌细胞对阿法替尼/西妥昔单抗的敏感性 在EGFR突变的激酶中确定完整的激酶功能所需的内在调节域。一种改进的 了解对EGFR抑制剂的敏感性和耐药性的机制和调节器将有望 使我们能够治疗/抑制进行性疾病的发展，并为生物学提供新的见解 由EGFR或其他突变受体酪氨酸激酶驱动的癌症。

EGFR mutant lung cancer is a subset of lung cancer with unique biological and clinical features. Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of EGFR experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or eriotinib (Tarceva), and overall median survival is about 30 months. However, no patients are cured. After about one year, acquired resistance develops. In previous work, we showed that in addition to primary drug-sensitive EGFR mutations, tumor cells from more than half of patients with such "acquired resistance" contain a recurrent second-site mutation (T790M) in the EGFR kinase domain. We also demonstrated using mouse models of lung cancer that T790M-mediated resistance could be overcome by a novel combination ofthe second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB clinical trial ofthis combination in humans, based upon our data, has now shown unprecedented activity in this patient cohort, with a 95% clinical benefit rate and a 35% confirmed radiographic response rate. The clinical findings have stimulated new and critical biological questions to address. Here, based upon promising new preliminary data, we aim to 1) elucidate the role of HER2 in mediating sensitivity of T790M-harboring EGFR mutant lung cancer cells to afatinib/cetuximab, and 2) identify in EGFR mutant kinases intrinsic regulatory domains required for full kinase function. An improved understanding of mechanisms and modulators of sensitivity and resistance to EGFR inhibitors will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.