title: A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines.
abstract: BACKGROUND
  Inhibiting the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of breast carcinoma cells, and this is linked to human epidermal growth factor receptor 2 (HER2) signaling pathways in models of simultaneous expression of FASN and HER2.
  
  
  METHODS
  In a xenograft model of breast carcinoma cells that are FASN+ and HER2+, we have characterised the anticancer activity and the toxicity profile of G28UCM, the lead compound of a novel family of synthetic FASN inhibitors. In vitro, we analysed the cellular and molecular interactions of combining G28UCM with anti-HER drugs. Finally, we tested the cytotoxic ability of G28UCM on breast cancer cells resistant to trastuzumab or lapatinib, that we developed in our laboratory.
  
  
  RESULTS
  In vivo, G28UCM reduced the size of 5 out of 14 established xenografts. In the responding tumours, we observed inhibition of FASN activity, cleavage of poly-ADPribose polymerase (PARP) and a decrease of p-HER2, p- protein kinase B (AKT) and p-ERK1/2, which were not observed in the nonresponding tumours. In the G28UCM-treated animals, no significant toxicities occurred, and weight loss was not observed. In vitro, G28UCM showed marked synergistic interactions with trastuzumab, lapatinib, erlotinib or gefitinib (but not with cetuximab), which correlated with increases in apoptosis and with decreases in the activation of HER2, extracellular signal-regulated kinase (ERK)1/2 and AKT. In trastuzumab-resistant and in lapatinib-resistant breast cancer cells, in which trastuzumab and lapatinib were not effective, G28UCM retained the anticancer activity observed in the parental cells.
  
  
  CONCLUSIONS
  G28UCM inhibits fatty acid synthase (FASN) activity and the growth of breast carcinoma xenografts in vivo, and is active in cells with acquired resistance to anti-HER2 drugs, which make it a candidate for further pre-clinical development.
authors.affiliation: Institut d'Investigació Biomèdica de Girona, E-17071 Girona, Spain. teresa.puig@udg.edu
authors.forename: Teresa
authors.initials: T
authors.lastname: Puig
authors.forename: Helena
authors.initials: H
authors.lastname: Aguilar
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Glòria
authors.initials: G
authors.lastname: Oliveras
authors.forename: Carlos
authors.initials: C
authors.lastname: Turrado
authors.forename: Sílvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: María Luz
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: Ander
authors.initials: A
authors.lastname: Urruticoechea
authors.forename: Ramon
authors.initials: R
authors.lastname: Colomer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005260:Female; D005707:Gallic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity / Q000031:analogs & derivatives; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D064429:Fatty Acid Synthases; D005707:Gallic Acid; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C572947:1,3-bis((3,4,5-trihydroxybenzoyl)oxy)naphthalene