Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors
Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors
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DOI：
10.1056/nejmoa051918
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发表时间：
2005-11-10
影响因子：
158.5
通讯作者：
Mischel, PS
中科院分区：
文献类型：
--
作者：
Mellinghoff, IK;Wang, MY;Mischel, PS
背景技术背景：表皮生长因子受体（EGFR）在胶质母细胞瘤中经常扩增，过度表达或突变，但只有10%至20%的患者对EGFR激酶抑制剂有反应。这些inhibitors的胶质母细胞瘤的反应机制是unknown.METHODS：我们测序激酶结构域的EGFR和人类EGFR 2型（Her 2/neu）基因和EGFR，EGFR缺失突变体III（EGFRvIII）的表达进行了分析，和肿瘤抑制蛋白PTEN在复发性恶性胶质瘤的患者谁收到了EGFR激酶抑制剂。我们确定了临床反应的分子相关性，验证他们在一个独立的数据集，并确定在vitro.RESULTS的分子异常的影响：49例复发性恶性胶质瘤谁与EGFR激酶抑制剂治疗，9肿瘤缩小至少25%。26例患者的治疗前组织可用于分子分析，其中7例有反应，19例在治疗期间迅速进展。在肿瘤中未检测到EGFR或Her 2/neu激酶结构域的突变。EGFRvIII和PTEN的共表达与临床反应显著相关（P
BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown.METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro.RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P