Activation of LXR β inhibits tumor respiration and is synthetically lethal with Bcl‐ xL inhibition

Abstract

Liver‐X‐receptor (LXR) agonists are known to bear anti‐tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti‐proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U‐13C‐glucose and U‐13C‐glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up‐regulates pro‐apoptotic Noxa in an ATF4‐dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient‐derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies.

Epigenetic Targeting of Mcl-1 Is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma

“…A limitation of the current work is that our studies did not include orthotopic in vivo studies, given that the microenvironment and the blood brain barrier might interfere with the efficacy of the treatment. These results are in keeping with earlier drug combinations involving BH3-mimetics [ 7 , 9 , 42 , 43 , 44 , 45 , 46 ].…”

“…Given the limited cell death induction by THZ1, we asked whether the killing efficacy of this compound might be enhanced in the presence of BH3-mimetics, such as ABT263. This hypothesis largely emerged from the fact that THZ1 suppressed Mcl-1 protein levels and that drugs that lower Mcl-1 levels have commonly been associated to enhance the efficacy of BH3-mimetics that target either Bcl-2, Bcl-xL, or both [ 7 , 9 , 42 , 43 , 44 , 45 , 46 ]. Consistently, we found that THZ1 and BH3-mimetics synergistically reduced the viability of GBM cells across a broad range of different model systems of human GBM.…”

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems

“…Although our experiments did not directly connect these two phenomena, previous work by us and others has demonstrated a tight linkage between energy deprivation (here mediated by dual loss of the major energetic pathways) and the activation of the integrated stress response [ 36 ]. In part, loss of ATP is linked due to accumulation of unfolded proteins given that proper maturation and protein synthesis depend on an appropriate state of energy within cells and altering this rheostat will affect the integrity of tumor cells [ 37 ].…”

The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives

“…LXR agonists represent novel means to counteract cholesterol levels in tumor cells, including glioblastoma and melanoma, by enhancing the excretion (increase in ABCA1) and, at the same time, by decreasing the resorption of cholesterol (decrease in LDL receptor) ( 121 ). Since LXR agonists upregulate the expression of the pro-apoptotic Bcl-2 family member, Noxa, BH3 mimetics (ABT263 and ABT199), and LXR agonists synergistically reduce cellular viability by enhancing apoptosis, resulting in a synergistic anti-proliferative effect across solid tumor cells ( 121 ).…”

“…LXR agonists represent novel means to counteract cholesterol levels in tumor cells, including glioblastoma and melanoma, by enhancing the excretion (increase in ABCA1) and, at the same time, by decreasing the resorption of cholesterol (decrease in LDL receptor) ( 121 ). Since LXR agonists upregulate the expression of the pro-apoptotic Bcl-2 family member, Noxa, BH3 mimetics (ABT263 and ABT199), and LXR agonists synergistically reduce cellular viability by enhancing apoptosis, resulting in a synergistic anti-proliferative effect across solid tumor cells ( 121 ). In preclinical models of diffuse intrinsic pontine glioma, a small molecule, menin inhibitor MI-2, has been proven to disrupt cholesterol homeostasis by inhibiting the conversion of 2,3-oxidosqualene to lanosterol, which also activates LXR to increase cholesterol efflux ( 136 ).…”