Department of Radiation Oncology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Medical School, Columbus, OH, USA.
Cancer Discov. 2011 Oct;1(5):442-56. doi: 10.1158/2159-8290.CD-11-0102. Epub 2011 Sep 15.
Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)-dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1-dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.
胶质母细胞瘤（GBM）是成人中最常见的恶性原发性脑肿瘤，也是所有癌症中最致命的一种。表皮生长因子受体（EGFR）突变（EGFRvIII）和磷酸肌醇 3-激酶（PI3K）过度激活在 GBM 中很常见，促进肿瘤生长和存活，包括通过固醇调节元件结合蛋白 1（SREBP-1）依赖性脂肪生成。胆固醇代谢在 GBM 发病机制中的作用、与 EGFR/PI3K 信号的关联及其作为潜在治疗靶点的可能性尚不清楚。在我们的研究中，通过对 GBM 细胞系、异种移植模型和 GBM 临床样本的研究，包括那些接受 EGFR 酪氨酸激酶抑制剂拉帕替尼治疗的患者的样本，揭示了一种通过低密度脂蛋白受体（LDLR）的 EGFRvIII 激活、PI3K/SREBP-1 依赖性肿瘤存活途径。使用肝 X 受体（LXR）激动剂 GW3965 靶向 LDLR 会导致 LDLR 的诱导型降解物（IDOL）介导的 LDLR 降解和 ABCA1 胆固醇外排转运蛋白的表达增加，在体内 GBM 模型中强烈促进肿瘤细胞死亡。这些结果表明，EGFRvIII 可以通过 PI3K/SREBP-1 依赖性上调 LDLR 促进肿瘤存活，并表明 LXR 激动剂在治疗 GBM 患者中的作用。
