A recent study utilizing human and mouse breast, colon and lung tumor models has shown that in response to withdrawal of therapy with sunitinib or sorafenib—which are receptor tyrosine kinase inhibitors considered to be antiangiogenic—tumors shift to lipogenesis, rapid regrowth and metastasis. Inhibiting lipogenesis with orlistat could reduce tumor regrowth, suggesting a new avenue to sensitize tumors. (Cell Metab. doi:10.1016/j.cmet.2014.05.022, 2014).
Agnes Noel and her colleagues performed global transcriptomic and proteomic analyses to examine the changes underlying the accelerated growth and metastasis observed after withdrawal of sunitinib or sorafenib therapy in mice bearing human MDA-MB-231 breast carcinoma xenografts. Similar changes in tumor growth have been observed in response to anti–VEGFR-2 and anti-VEGF therapies. Analysis of tumors during sunitinib or sorafenib treatment showed increased glycolysis. However, upon treatment withdrawal, lipid metabolism and regulation were altered, resulting in a boost in fatty acid, pyruvate and amino acid metabolism. Fatty acid synthase (FASN) expression increased, suggesting a shift toward de novo lipogenesis.
The authors then treated MDA-MB-231 or HT-29 xenografts and syngeneic mouse models with orlistat, a fatty acid synthase inhibitor, after sunitinib therapy withdrawal, and they noted reduced tumor growth and inhibited metastasis formation without effects on whole-body metabolic profiles.
Treatment with antiangiogenic therapies can lead to more aggressive tumors after therapy withdrawal. Future studies may opt to employ FASN inhibition after therapy cessation to avert such deleterious effects in patients.
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Simpson, K. Cancer metabolism: Lipid addiction. Nat Med 20, 813 (2014). https://doi.org/10.1038/nm.3659
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