Editors' ChoiceCancer

Collaborating tumor cells overcome multitargeted antiangiogenic therapies

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Science Translational Medicine  11 May 2016:
Vol. 8, Issue 338, pp. 338ec77
DOI: 10.1126/scitranslmed.aaf9190

Angiogenesis, the process by which tumors stimulate the growth of new blood vessels to supply necessary oxygen and nutrients for growth, is a hallmark of cancer whose inhibition has the potential to result in tumor starvation and death. The discovery that signaling through the vascular endothelial growth factor (VEGF) receptor plays a rate-limiting role in tumor angiogenesis led to the development of drugs like bevacizumab, a humanized monoclonal antibody targeting VEGF-A, to which some cancers respond clinically. However, responses to selective VEGF pathway antagonists are typically incomplete and transient, and evidence from preclinical models suggests that resistance is driven by the activation of alternative angiogenesis signaling pathways, such as those downstream of fibroblast growth factors (FGFs) and platelet-derived growth factors (PDGFs). On the basis of these findings, a suite of multitargeted kinase inhibitors (MTKIs)—such as sorafenib, sunitinib, axitinib, and nintedanib, which coordinately inhibit multiple VEGF-dependent and -independent pathways—have been developed and advanced clinically. Although these drugs are promising, resistance to MTKIs also eventually emerges, but its mechanistic basis remains unclear.

Three recent integrated studies in Cell Reports shed critical light on the basis for resistance to MTKIs. In model systems that included breast, pancreatic neuroendocrine, and renal cancers, investigators uncovered similar patterns, wherein MTKI resistance did not involve revascularization but instead produced a characteristic spatial pattern in which cells in avascular areas lacking oxygen up-regulated glycolysis through the glucose transporter GLUT1. These glycolytic cells produced increased amounts of lactate, which was exported via the transporter MCT4 and could be subsequently internalized via the lactate importer MCT1 on proximal cells residing in oxygenated regions, where it would then drive oxidative metabolism. This collective phenomenon, originally discovered as a mechanism of spontaneous hypoxic adaptation in tumors through the pioneering work of Mark Dewhirst and colleagues, has been termed “metabolic symbiosis.” The three new studies by Allen et al., Pisarsky et al., and Jiménez-Valerio et al. revealed that pharmacological inhibition of metabolic symbiosis using inhibitors of glycolysis or the mammalian target of rapamycin complex 1 (mTORC1) pathway, as well as genetic inhibition of MCT4, improved the depth and duration of antitumor activity of various MTKIs. Further, the study of Jiménez-Valerio et al. provided compelling evidence that metabolic symbiosis is a predominant mechanism of resistance to MTKI therapy in human patients with renal cell carcinoma.

These studies are likely to have important translational implications. First, they support the hypothesis that MTKIs can more durably suppress angiogenesis than selective VEGF pathway antagonists. Second, they suggest that strategies that block metabolic symbiosis may accentuate the clinical activity of antiangiogenic therapy. Last, they suggest that although the inhibition of glycolysis and the mTORC1 pathway have the potential to disrupt symbiosis, direct inhibitors of the lactate transporters MCT1 and MCT4 may have more profound activity in this setting, an important observation given that small molecule inhibitors of these targets are currently in development.

E. Allen et al., Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep. 10.1016/j.celrep.2016.04.029 (2016). [Full Text]

L. Pisarsky et al., Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep. 10.1016/j.celrep.2016.04.028 (2016). [Full Text]

G. Jiménez-Valerio et al., Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients. Cell Rep. 10.1016/j.celrep.2016.04.015 (2016). [Full Text]

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