Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

• Tumors can escape anti-angiogenic therapy with multi-kinase inhibitors
• A glycolytic shift underlies resistance against multi-kinase inhibitors
• Metabolic symbiosis between hypoxic and oxygenated cells inspires therapy resistance
• Inhibition of glycolysis or lactate export collapses metabolic symbiosis

SummaryDespite 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.

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