胶质母细胞瘤对表皮生长因子受体（EGFR）激酶抑制剂反应的分子决定因素。

Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.

作者信息

Mellinghoff Ingo K, Wang Maria Y, Vivanco Igor, Haas-Kogan Daphne A, Zhu Shaojun, Dia Ederlyn Q, Lu Kan V, Yoshimoto Koji, Huang Julie H Y, Chute Dennis J, Riggs Bridget L, Horvath Steve, Liau Linda M, Cavenee Webster K, Rao P Nagesh, Beroukhim Rameen, Peck Timothy C, Lee Jeffrey C, Sellers William R, Stokoe David, Prados Michael, Cloughesy Timothy F, Sawyers Charles L, Mischel Paul S

机构信息

Department of Molecular and Medical Pharmacology and Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles 90095-1732, USA.

出版信息

N Engl J Med. 2005 Nov 10;353(19):2012-24. doi: 10.1056/NEJMoa051918.

DOI:10.1056/NEJMoa051918

PMID:16282176

Abstract

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<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib.

CONCLUSIONS

Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.

摘要

背景

表皮生长因子受体（EGFR）在胶质母细胞瘤中常出现扩增、过表达或突变，但只有10%至20%的患者对EGFR激酶抑制剂有反应。胶质母细胞瘤对这些抑制剂产生反应的机制尚不清楚。

方法

我们对EGFR和人表皮生长因子受体2（Her2/neu）基因的激酶结构域进行测序，并分析接受EGFR激酶抑制剂治疗的复发性恶性胶质瘤患者中EGFR、EGFR缺失突变体变体III（EGFRvIII）和肿瘤抑制蛋白PTEN的表达。我们确定了临床反应的分子相关性，在一个独立的数据集中对其进行验证，并在体外鉴定了分子异常的影响。

结果

49例接受EGFR激酶抑制剂治疗的复发性恶性胶质瘤患者中，9例肿瘤缩小至少25%。26例患者的预处理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。肿瘤中未检测到EGFR或Her2/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<0.001；优势比，51；95%置信区间，4至669）。这些发现在另一机构接受类似胶质母细胞瘤治疗的33例患者中得到验证（P=0.001；优势比，40；95%置信区间，3至468）。在体外，EGFRvIII和PTEN的共表达使胶质母细胞瘤细胞对厄洛替尼敏感。