Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib
Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib
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DOI：
10.1093/jnci/dji161
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发表时间：
2005-06-15
影响因子：
10.3
通讯作者：
Stokoe, D
中科院分区：
文献类型：
--
作者：
Haas-Kogan, DA;Prados, MD;Stokoe, D
背景表皮生长因子受体（EGFR）酪氨酸激酶抑制剂厄洛替尼（也称为特罗凯或OSI-774）在恶性胶质瘤中显示出有希望的反应率。我们研究了EGFR和下游信号成分的表达与恶性胶质瘤对厄洛替尼的反应之间的关系，在一项厄洛替尼单独给药或与烷化剂替莫唑胺联合给药的I期试验中。研究方法：采用免疫组化法检测胶质瘤患者标本中EGFR和配体非依赖性EGFRvIII突变蛋白以及磷酸化蛋白激酶B（PKB）/Akt的表达。荧光原位杂交检测EGFR基因扩增情况。通过聚合酶链反应扩增和测序来评估PTEN和EGFR的突变。每2个月通过连续磁共振成像评价反应。Cochran-Mantel-Haenzel检验用于评估生物标志物状态与缓解之间的相关性。所有统计学检验均为双侧检验。结果：41例胶质瘤患者中，8例对治疗有反应。对厄洛替尼的反应与EGFR表达（P = 0.07）和EGFR扩增（P = 0.08）相关。在最初诊断为多形性胶质母细胞瘤的29例患者中，这些相关性更强，具有统计学意义（分别为P = .03和P = .02）。在6例有足够肿瘤组织的应答者中，无EGFRvIII突变。22个具有高水平磷酸化PKB/Akt的肿瘤中没有一个对厄洛替尼治疗有反应，而18个具有低水平磷酸化PKB/Akt的肿瘤中有8个对厄洛替尼治疗有反应（P < .001）。磷酸化PKB/Akt水平也与疾病进展时间相关（P <0.001）。结论：在胶质瘤患者中，EGFR表达水平高、磷酸化PKB/Akt水平低的多形性胶质母细胞瘤患者对厄洛替尼治疗的反应优于EGFR表达水平低、磷酸化PKB/Akt水平高的患者。
Background. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (also known as Tarceva or OSI-774) has shown promising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide. Methods: Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry. EGFR gene amplification was evaluated by fluorescence in situ hybridization. Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplification and sequencing. Response was evaluated by sequential magnetic resonance imaging every 2 months. The Cochran-Mantel-Haenzel test was used to assess associations between bio-marker status and response. All statistical tests were two-sided. Results: Of 41 glioma patients, eight responded to treatment. Response to erlotinib was associated with EGFR expression (P = .07) and EGFR amplification (P = .08). These associations were stronger and statistically significant among the 29 patients initially diagnosed with glioblastoma multiforme (P = .03 and P = .02, respectively). Among six responders with sufficient tumor tissue, none had EGFRvIII mutations. None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment, whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment (P < .001). The level of phosphorylated PKB/Akt was also associated with time to progression (P < .001). Conclusions: Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt.