Laboratory of Brain Tumor Biology and Genetics, Department of Neurosurgery, LausanneUniversity Hospital and University of Lausanne, Lausanne, Switzerland.
Mol Cancer Ther. 2011 Jun;10(6):1102-12. doi: 10.1158/1535-7163.MCT-11-0048. Epub 2011 Apr 6.
Amplification of the epidermal growth factor receptor (EGFR) gene is one of the most common oncogenic alterations in glioblastoma (45%) making it a prime target for therapy. However, small molecule inhibitors of the EGFR tyrosine kinase showed disappointing efficacy in clinical trials for glioblastoma. Here we aimed at investigating the molecular effects of the tyrosine kinase inhibitor gefitinib on the EGFR signaling pathway in human glioblastoma. Twenty-two patients selected for reoperation of recurrent glioblastoma were treated within a phase II trial for 5 days with 500 mg gefitinib before surgery followed by postoperative gefitinib until recurrence. Resected glioblastoma tissues exhibited high concentrations of gefitinib (median, 4.1 μg/g), 20 times higher than respective plasma. EGFR-pathway activity was evaluated with phosphorylation-specific assays. The EGFR was efficiently dephosphorylated in treated patients as compared to a control cohort of 12 patients. However, no significant effect on 12 pathway constituents was detected. In contrast, in vitro treatment of a glioblastoma cell line, BS-153, with endogenous EGFRwt amplification and EGFRvIII expression resulted not only in dephosphorylation of the EGFR, but also of key regulators in the pathway such as AKT. Treating established xenografts of the same cell line as an in vivo model showed dephosphorylation of the EGFR without affecting downstream signal transductors, similar to the human glioblastoma. Taken together, gefitinib reaches high concentrations in the tumor tissue and efficiently dephosphorylates its target. However, regulation of downstream signal transducers in the EGFR pathway seems to be dominated by regulatory circuits independent of EGFR phosphorylation.
表皮生长因子受体 (EGFR) 基因的扩增是胶质母细胞瘤（45%）中最常见的致癌改变之一，使其成为治疗的主要靶点。然而，EGFR 酪氨酸激酶的小分子抑制剂在胶质母细胞瘤的临床试验中疗效令人失望。在这里，我们旨在研究酪氨酸激酶抑制剂吉非替尼对人类胶质母细胞瘤中 EGFR 信号通路的分子影响。22 名因复发性胶质母细胞瘤而选择再次手术的患者在一项 II 期临床试验中接受治疗，在手术前用 500mg 吉非替尼治疗 5 天，然后在手术后继续用吉非替尼治疗，直到复发。切除的胶质母细胞瘤组织显示出高浓度的吉非替尼（中位数为 4.1μg/g），是相应血浆的 20 倍。使用磷酸化特异性测定法评估 EGFR 通路活性。与 12 名患者的对照组相比，接受治疗的患者 EGFR 被有效去磷酸化。然而，没有检测到对 12 种通路成分的显著影响。相比之下，在体外用内源性 EGFRwt 扩增和 EGFRvIII 表达的胶质母细胞瘤细胞系 BS-153 治疗不仅导致 EGFR 去磷酸化，而且还导致通路中的关键调节剂如 AKT 去磷酸化。作为体内模型的相同细胞系的已建立异种移植物的治疗显示 EGFR 的去磷酸化而不影响下游信号转导器，类似于人类胶质母细胞瘤。总之，吉非替尼在肿瘤组织中达到高浓度，并有效地使靶标去磷酸化。然而，EGFR 通路下游信号转导器的调节似乎由独立于 EGFR 磷酸化的调节回路主导。
