A Fatty Acid Synthase Inhibitor Shows New Anticancer Mechanisms

The pharmacological modulation of proteins and molecules related up-regulation of FASN in precursor lesionsmight represent an obligatory to cancer is an important goal for translational science. Fatty acid synthase (FASN) is a complex dimeric protein that converts acetyl-CoA and malonyl-CoA into palmitic acid in a NADPH-dependent reaction in mammalian cells (Maier et al., 2006). Many cancers present a strong FASN expression and high enzymatic activity, and in recent years FASN has emerged as a relevant anticancer target. So far, several compounds have been reported to inhibit the enzymatic activity of FASN and to have an effect on the growth of malignant cells. Some of these compounds exhibit pharmacological limitations or induce weight loss, preventing their development as systemic drugs. In this issue of EBioMedicine, Ventura et al. report the characterization of the anti-tumor activity of TVB-3166, a potent and orally available FASN inhibitor that may provide a novel approach for cancer therapy (Ventura et al., 2015). The authors observed that FASN inhibition with TVB-3166 was able to induce apoptosis, to inhibit anchorageindependent cell growth under lipid-rich conditions, and to inhibit in vivo xenograft tumor growth in a dose-dependent manner without affecting non-cancer cells. FASN plays a critical role in a number of metabolic functions by catalyzing the terminal steps in the synthesis of long-chain saturated fatty acids. There is a strong FASNexpression andhigh enzymatic activity in many cancers especially in carcinomas (Sebastiani et al., 2006), while FASN is expressed at low levels in most normal tissues, except the liver, adipose tissue, and lactating mammary gland (Sul and Wang, 1998), suggesting that cancer cells are more dependent on de novo palmitate synthesis catalyzed by FASN than normal cells (Menendez and Lupu, 2007). Palmitate and palmitate-derived lipids are essential components in cancer cell proliferation and survival as they provide energy metabolism and storage, membrane biosynthesis, and architecture and protein localization and activity. The well-documented upregulation of FASN in many human cancers as well as its association with poor clinical outcome (Witkiewicz et al., 2008) both strengthen the hypothesis that FASN is involved in the development, maintenance, and enhancement of the malignant phenotype. Interestingly, increased FASN expression has also been observed in some pre-neoplastic lesions and increases with tumor progression, supporting the hypothesis that the early