Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy

Despite the approval of several anti-angiogenic therapies for the treatment of cancer patients, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. In the case of the targeted inactivation of an individual pro-angiogenic pathway, such as vascular endothelial growth factor (VEGF)-mediated signaling, tumors switch to employ other pro-angiogenic factors and signaling pathways, for example fibroblast growth factors (FGF), Bv8/Prokineticin, interleukin 33 and others. We have studied the anti-angiogenic efficacy of the anti-angiogenic multi-kinase inhibitor nintedanib in a mouse model of breast cancer. Nintedanib demonstrates a potent anti-angiogenic effect. However, after an initial repression of tumor expansion, tumors resume growth in the absence of active tumor angiogenesis, suggesting a novel mechanism of therapy resistance whereby tumor cells proliferate without proper vascularization. Gene expression profiling analysis of flow cytometry-sorted tumor cells reveals a metabolic reprogramming towards anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, alternation between hypoxic, glycolytic areas and normoxic areas in the nintedanib-treated tumors suggests the establishment of metabolic symbiosis, further illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters implicated in lactate exchange in glycolytic tumors. Accordingly, ablation of MCT4 expression surmounts resistance to anti-angiogenic therapy. Our results suggest a mechanism of glycolytic symbiosis to overcome a potent anti-angiogenic therapy with a multi-kinase inhibitor. Hence, targeting metabolic symbiosis may be an attractive avenu