An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.
An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.
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DOI：
10.1016/j.ccell.2016.09.008
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发表时间：
2016-11-14
期刊：
影响因子：
50.3
通讯作者：
Mischel PS
中科院分区：
文献类型：
--
作者：
Villa GR;Hulce JJ;Zanca C;Bi J;Ikegami S;Cahill GL;Gu Y;Lum KM;Masui K;Yang H;Rong X;Hong C;Turner KM;Liu F;Hon GC;Jenkins D;Martini M;Armando AM;Quehenberger O;Cloughesy TF;Furnari FB;Cavenee WK;Tontonoz P;Gahman TC;Shiau AK;Cravatt BF;Mischel PS
靶向生长因子受体的小分子抑制剂未能显示出对脑癌的疗效，可能是由于无法在中枢神经系统中达到足够的药物水平。针对非癌基因肿瘤的共同依赖提供了另一种方法，特别是如果可以识别具有高脑穿透性的药物。在这里，我们证明了高致死性脑癌胶质母细胞瘤（GBM）的生存明显依赖胆固醇，使这些肿瘤对肝X受体（LXR）激动剂依赖性细胞死亡敏感。我们发现LXR-623是一种临床可行的，高度脑渗透的lxr α-部分/LXRβ-完全激动剂，以LXRβ和胆固醇依赖的方式选择性杀死GBM细胞，导致肿瘤消退和延长小鼠模型的生存期。因此，代谢相互依赖提供了一种药物手段来杀死中枢神经系统中生长因子激活的癌症。
Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to inability to achieve sufficient drug levels in the CNS. Targeting non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRα-partial/LXRβ-full agonist selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.