2026-06-14T03:42:03Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/78912024-11-29T22:50:48Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Navarro, Paloma author Bueno, Maria J author Zagorac, Ivana author Mondejar, Tamara author Sanchez, Jesus author Mouron, Silvana Andrea author Muoz Peralta, Javier author Gómez-López, Gonzalo author Jimenez-Renard, Veronica author Mulero Francisca, F author Chandel, Navdeep S author Quintela Fandino, Miguel Angel author 2016-06-21 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. Cell Rep. 2016;15(12):2705-18 10.1016/j.celrep.2016.05.052 2211-1247 22111247 Cell reports 27292634 http://hdl.handle.net/20.500.12105/7891 Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics