Cancer metabolism reprogramming in response to anti-angiogenic therapy

In this study, we have explored the tumor adaptation to antiangiogenic therapy with the multitarget receptor tyrosine kinase inhibitors (RTKIs) Sunitinib and sorafenib. These RTKIs are currently in clinical use for multiple tumor types and confer increased overall or progression-free survival. However, antiangiogenic drugs demonstrate only relatively modest survival benefits and transient responses to treatment. Furthermore, preclinical studies suggest that RTKIs withdrawal results in accelerated tumor progression and metastasis. By applying the RTKIs treatment to 5 preclinical models of cancer development with global screening technologies, we found that tumors shift their metabolism during antiangiogenic therapy and acquire more aggressive phenotype after treatment cessation. We found that accelerated tumor growth and metastasis upon RTKIs withdrawal was associated with decreased glucose metabolism, increased lipid metabolism, and activation of the tricarboxylic acid (TCA) cycle. In particular, withdrawal of RTKIs resulted in elevated levels of fatty acid synthase (FASN) and acetyl-CoA carboxylase and adipocyte accumulation in tumors. Antiangiogenic therapy induced a metabolic shift in cancer and stromal cells 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 suppressed the RTKIs withdrawal–associated tumor regrowth and metastasis. We will discuss the role for lipid metabolism in tumor adaptation to antiangiogenic therapy withdrawal.