Abstract
Adaptation to antiangiogenic therapy withdrawal involves a metabolic shift to de novo lipogenesis.
Major finding: Adaptation to antiangiogenic therapy withdrawal involves a metabolic shift to de novo lipogenesis.
Clinical relevance: RTKI-induced metabolic changes may explain the limited efficacy of antiangiogenic therapy.
Impact: Fatty acid synthase inhibition may reduce relapse after antiangiogenic therapy withdrawal.
Antiangiogenic therapies such as the multitarget receptor tyrosine kinase inhibitors (RTKI) sunitinib and sorafenib are currently in clinical use for multiple tumor types and confer increased overall or progression-free survival. However, antiangiogenic drugs demonstrate relatively modest survival benefits, and most patients respond only transiently or do not respond to treatment at all. Additionally, preclinical studies suggest that RTKI withdrawal results in accelerated tumor progression and metastasis, demonstrating the need for a more comprehensive understanding of the mechanisms of response and resistance to RTKIs. Utilizing multiple cancer models coupled with transcriptomic, proteomic, and metabolomic approaches, Sounni, Cimino, and colleagues found that accelerated tumor growth and metastatic dissemination upon RTKI withdrawal was associated with decreased glucose metabolism, increased lipid metabolism, and activation of the tricarboxylic acid (TCA) cycle. In particular, withdrawal of sunitinib or sorafenib resulted in elevated levels of fatty acid synthase (FASN) and acetyl-CoA carboxylase and adipocyte accumulation in tumor xenografts. Antiangiogenic therapy induced a metabolic shift in cancer cells and stromal cells, including endothelial cells and cancer-associated fibroblasts, to a glycolytic and hypoxic state during treatment, which was reversed upon therapy withdrawal, resulting in a shift to de novo lipogenesis and increased TCA cycle activity to promote tumor regrowth. Targeting lipid metabolism using the FASN inhibitor orlistat or by specific knockdown of FASN was sufficient to suppress RTKI withdrawal–associated tumor regrowth and metastatic dissemination in multiple mouse tumor models without significantly affecting whole-body metabolism, suggesting that the malignant shift to lipid metabolism occurred only in tumor cells. In sum, these data demonstrate a role for lipid metabolism in tumor adaptation to antiangiogenic therapy withdrawal, and identify FASN as a potential therapeutic target to improve the efficacy of antiangiogenic treatment.