Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics

Epithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors downregulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic, and phosphoproteomic study revealed that this metabolic switch is mediated by downregulation of HIF1α and AKT and upregulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, leading to metabolic synthetic lethality. Our study uncovers mechanistic insights in the process of tumor resistance to TKIs and may have clinical applicability. [Display omitted] •Anti-angiogenics can correct hypoxia in breast and lung tumors•Normoxic tumors shut down glycolysis and rely on mitochondrial metabolism•Mitochondrial metabolism is essential for tumor survival when normoxic•Targeting mitochondrial metabolism is synergistic with antiangiogenics Navarro et al. show that tumors treated with antiangiogenics can correct hypoxia and downregulate aerobic glycolysis. Tumors show metabolic plasticity, switching to mitochondrial metabolism, mediated by AMPK, PKA, and PPARα. Despite the adaptation, mitochondrial metabolism becomes essential for tumor survival. Thus, anti-mitochondrial agents induce metabolic synthetic lethality in this situation.