Navarro, PalomaBueno, Maria JZagorac, IvanaMondejar, TamaraSanchez, JesusMouron, Silvana AndreaMuoz Peralta, JavierGómez-López, GonzaloJimenez-Renard, VeronicaMulero Francisca, FChandel, Navdeep SQuintela Fandino, Miguel Angel2019-07-112019-07-112016-06-21Cell Rep. 2016;15(12):2705-1822111247http://hdl.handle.net/20.500.12105/7891Epithelial 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.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/Angiogenesis InhibitorsAnimalsCell ProliferationCell RespirationCellular ReprogrammingDisease Models, AnimalDown-RegulationDrug Resistance, NeoplasmFatty AcidsFemaleGlucoseGlycolysisHumansKetone BodiesMetabolomeMice, Inbred C57BLMice, NudeMitochondriaMitochondrial DegradationNeoplasmsOxygenPhenylurea CompoundsPhosphoproteinsProtein Kinase InhibitorsPyridinesSignal TransductionAtribución-NoComercial-CompartirIgual 4.0 Internacional2729263415122705-1810.1016/j.celrep.2016.05.0522211-1247Cell reportsopen access