Activation of LXR? Inhibits Tumor Respiration and is Synthetically Lethal with Bcl-xL Inhibition

Liver-X-receptor agonists (LXR) 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 effects of BH3-mimetics in solid tumor malignancies. Extracellular flux analysis and carbon tracing experiments (U-13C-Glucose and U-13C-Glutamine) reveal that within 5h activation of LXRb 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. 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.