1Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
Sci Signal. 2009 Dec 15;2(101):ra82. doi: 10.1126/scisignal.2000446.
Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1, possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.
胶质母细胞瘤是最常见的恶性脑肿瘤，也是最难治疗的致命癌症之一。尽管表皮生长因子受体 (EGFR) 突变在胶质母细胞瘤中很常见，但它们的临床相关性尚不清楚。对接受 EGFR 抑制剂拉帕替尼治疗的患者的肿瘤研究表明，EGFR 诱导脂肪酸合成的主要转录调节剂固醇调节元件结合蛋白 1 (SREBP-1) 的切割和核易位。这种反应是由 Akt 介导的；然而，来自接受雷帕霉素治疗的患者的临床数据表明，SREBP-1 的激活与雷帕霉素靶蛋白复合物 1 无关，这可能解释了雷帕霉素在治疗此类肿瘤方面效果不佳的原因。没有持续激活 EGFR 信号的胶质母细胞瘤对脂肪酸合成的抑制具有抗性，而引入持续激活的 EGFR 突变形式 EGFRvIII 则使肿瘤异种移植物对细胞死亡敏感，羟甲基戊二酰辅酶 A 还原酶抑制剂阿托伐他汀可增强这种敏感性。这些结果确定了以前未描述的 EGFR 介导的促生存代谢途径，并为治疗 EGFR 激活的胶质母细胞瘤提供了新的治疗方法。
