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.
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Paloma
P
Navarro
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Maria J
MJ
Bueno
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Ivana
I
Zagorac
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Tamara
T
Mondejar
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Jesus
J
Sanchez
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Silvana
S
Mourón
Proteomics Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Javier
J
Muñoz
Bioinformatics Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Gonzalo
G
Gómez-López
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Veronica
V
Jimenez-Renard
Molecular Imaging Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
Francisca
F
Mulero
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Navdeep S
NS
Chandel
Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, 28029 Madrid, Spain. Electronic address: mquintela@cnio.es.
Miguel
M
Quintela-Fandino
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism; D055442:Metabolome / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D005227:Fatty Acids; D007657:Ketone Bodies; D010671:Phenylurea Compounds; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib; D005947:Glucose; D010100:Oxygen