An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers

被引：262

作者：

Villa, Genaro R. ^{[1
,2
,3
]}

Hulce, Jonathan J. ^{[4
]}

Zanca, Ciro ^{[3
]}

Bi, Junfeng ^{[3
]}

Ikegami, Shiro ^{[3
]}

Cahill, Gabrielle L. ^{[3
]}

Gu, Yuchao ^{[1
,3
]}

Lum, Kenneth M. ^{[4
]}

Masui, Kenta ^{[5
]}

Yang, Huijun ^{[3
]}

Rong, Xin ^{[6
]}

Hong, Cynthia ^{[6
]}

Turner, Kristen M. ^{[3
]}

Liu, Feng ^{[3
]}

Hon, Gary C. ^{[3
]}

Jenkins, David ^{[13
]}

Martini, Michael ^{[4
]}

Armando, Aaron M. ^{[7
]}

Quehenberger, Oswald ^{[7
,8
]}

Cloughesy, Timothy F. ^{[9
]}

Furnari, Frank B. ^{[3
,10
,11
]}

Cavenee, Webster K. ^{[3
,8
,11
]}

Tontonoz, Peter ^{[6
,12
]}

Gahman, Timothy C. ^{[13
]}

Shiau, Andrew K. ^{[13
]}

Cravatt, Benjamin F. ^{[4
]}

Mischel, Paul S. ^{[3
,10
,11
]}

机构：

[1] David Geffen UCLA Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] David Geffen UCLA Sch Med, Med Scientist Training Program, Los Angeles, CA 90095 USA

[3] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[4] Scripps Res Inst, Dept Physiol Chem, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[5] Tokyo Womens Med Univ, Dept Pathol, Tokyo 1628666, Japan

[6] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[7] Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA

[8] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[10] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA

[11] Univ Calif San Diego, Sch Med, Moores Canc Ctr, La Jolla, CA 92093 USA

[12] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA

[13] Univ Calif San Diego, Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA

来源：

CANCER CELL | 2016年 / 30卷 / 05期

关键词：

LIVER X RECEPTORS; SMALL-MOLECULE; GLIOBLASTOMA; GROWTH; INHIBITION; NEURONS; EFFLUX; CELLS; ATHEROSCLEROSIS; PROLIFERATION;

D O I：

10.1016/j.ccell.2016.09.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their 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 LXR alpha-partial/LXR beta-full agonist selectively kills GBM cells in an LXR beta- 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.

引用

页码：683 / 693

页数：11

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