title: Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression.
abstract: Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics.
  
  
  BACKGROUND
  Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Ventura
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Kasia
authors.initials: K
authors.lastname: Mordec
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Joanna
authors.initials: J
authors.lastname: Waszczuk
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Zhaoti
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Lai
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Fridlib
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Buckley
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: George
authors.initials: G
authors.lastname: Kemble
authors.affiliation: 3-V Biosciences, Menlo Park, CA, United States.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Heuer
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D019308:Palmitic Acid; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I
keywords: Beta-catenin; CRC, colorectal cancer; DMEM, Dulbecco's Modified Eagle's Medium; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; Fatty acid synthase; HUVEC, human umbilical vein endothelial cells; Inhibitor; KRAS; LC–MS, liquid chromatography–mass spectrometry; Lipid raft; MEM, minimal essential media; MYC; NADPH, nicotinamide adenine dinucleotide phosphate; NSCLC, non-small-cell lung cancer; PBS, phosphate buffered saline; TGI, tumor growth inhibition