2024-03-29T06:31:32Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/78912023-10-06T08:15:13Zcom_20.500.12105_2174com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_2175
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
22111247
http://hdl.handle.net/20.500.12105/7891
27292634
10.1016/j.celrep.2016.05.052
2211-1247
Cell reports
Targeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenics