Kemble, George

Abstract Fatty acid synthase (FASN) is a novel therapeutic target for cancer as it has increased expression in many different types of cancers. There has been significant understanding that cancer cells can hijack and modify tightly regulated metabolic pathway for its own survival. FASN is the enzyme that synthesizes palmitate from malonyl-CoA for energy storage, structure and biomolecules. FASN expression is low to undetectable in normal cells with the exception of liver and adipose tissue. In this study, we investigated the role of FASN in breast cancer cells. We observed that in highly expressing FASN breast cancer cells, TVB-3166, FASN inhibitor, results in a decrease in cellular proliferation and an increase in cellular death. FASN inhibition increased reactive oxygen species (ROS) and altered NADPH/NADP+ ratio. Increase in ROS and NADPH have been linked to the intrinsic apoptosis pathway. Additionally, there is an increase in expression of the BH3-only proteins Bim, Puma and Noxa, leading to the permeabilization of the mitochondria and the release of cytochrome c. Furthermore, after prolong exposure to TVB-3166 a number of cells enter into a senescent state. This was observed the in detection of β-galactosidase and confirmed by the expression of senescent markers including ARF, INK4A, and CIP. Additionally, when the cells were treated with a CDK4/6 inhibitor in combination with the FASN inhibitor TVB-3166, an increase in stress induced premature senescence was observed. Our data demonstrates that inhibition of FASN induces intrinsic apoptosis while it stimulates cellular senescence to the apoptotic resistant cells. Therefore, the ability for TVB-3166 to both eradicate and overturn cell growth makes it potential therapeutic modality. Citation Format: Travis Van der Steen, George Kemble, Ruth Lupu. Targeting fatty acid synthase induces apoptosis and senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 708.

Abstract Increased de novo lipogenesis due to enhanced expression of several lipogenic enzymes has been found in many types of human cancers. Fatty acid synthase (FASN), the key enzyme in the de novo lipogenesis pathway, is one of the most commonly over-expressed lipogenic enzymes. Studies in the past decade have recognized FASN overexpression as a molecular marker for poor prognosis and malignant phenotype of many cancers. Tumor-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, has also been suggested to play an active part in the development, maintenance, and metastatic progression of human cancers. More recently, FASN has been implicated in contributing to cellular resistance to several anticancer treatments. A variety of agents have been developed to target lipogenic enzymes and the key regulators involved in lipid metabolism in cancer cell for therapeutic purposes. The development of several FASN inhibitors has been reported from both academic labs and industries. When used in in vitro, xenograft and genetically induced mouse model studies, these inhibitors have supported FASN as an excellent target. A new generation of FASN inhibitors was developed at 3-V Biosciences that are highly specific, reversible inhibitors of FASN. One compound in this series, TVB-2640, is orally bioavailable and has progressed into Phase 1 clinical studies. The effect of two anti-FASN drugs in this series, TVB-3150 and TVB-3199 were tested for their effect on breast cancer cells. We demonstrated that the EC50 is between 9-50 nM, depending on the drug and the tested cell line. We then demonstrated that the drugs inhibited the anchorage-dependent and -independent growth of FASN expressing cells in a dose dependent manner. The apparent mechanism by which the FASN inhibitors promote inhibition of growth is by inducing apoptotic cell death in a time- and dose-dependent manner that involves regulation of apoptotic and pro-apoptotic proteins. Furthermore, the combination of the anti-FASN drugs with small molecule inhibitors of the antiapoptotic proteins Bcl-2 and Bcl-xL significantly increased the apoptotic effect in a synergistic manner compared to either of the synthetic inhibitors alone. In vivo studies demonstrate tumor growth inhibition without toxicity. Clinical development of a first-in-class, orally active, potent, and reversible FASN inhibitor as a novel cancer therapeutic is ongoing. Citation Format: Ruth Lupu, Anatilde Gonzalez Guerrico, Ashwani Khurana, Timothy Heuer, George Kemble, Chandra Mohan KVP. Small-molecule FASN inhibitors promote growth inhibition growth and apoptosis of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2014-2713