Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

Laura Pisarsky, Ruben Bill, Ernesta Fagiani, Sarah Dimeloe, Ryan WIlliam Goosen, Jörg Hagmann, Christoph Hess, Gerhard Christofori

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)
140 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)1161-1174
JournalCell Reports
Volume15
Issue number6
Early online date28 Apr 2016
DOIs
Publication statusPublished - 10 May 2016

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