title: Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy.
abstract: Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Pisarsky
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Ruben
authors.initials: R
authors.lastname: Bill
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Ernesta
authors.initials: E
authors.lastname: Fagiani
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dimeloe
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Ryan William
authors.initials: RW
authors.lastname: Goosen
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hagmann
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hess
authors.affiliation: Department of Biomedicine, University of Basel, 4058 Basel, Switzerland. Electronic address: gerhard.christofori@unibas.ch.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C498648:Slc16a4 protein, mouse; C530716:nintedanib