title: Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs.
abstract: Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies.
authors.affiliation: New Therapeutic Targets Lab (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Blancafort
authors.affiliation: New Therapeutic Targets Lab (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Giró-Perafita
authors.affiliation: New Therapeutic Targets Lab (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain; Catalan Institute of Oncology, Hospital Dr. Josep Trueta, Girona, Spain.
authors.forename: Glòria
authors.initials: G
authors.lastname: Oliveras
authors.affiliation: New Therapeutic Targets Lab (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Palomeras
authors.affiliation: Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Turrado
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGi, Girona, Spain.
authors.forename: Òscar
authors.initials: Ò
authors.lastname: Campuzano
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Carrión-Salip
authors.affiliation: Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGi, Girona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL), Hospitalet de Llobregat-Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Palafox
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL), Hospitalet de Llobregat-Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gómez-Miragaya
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL), Hospitalet de Llobregat-Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: González-Suárez
authors.affiliation: New Therapeutic Targets Lab (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Puig
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors*; D005260:Female; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D000068878:Trastuzumab / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002392:Catechin; D054890:Fatty Acid Synthase, Type I; D005707:Gallic Acid; D000077341:Lapatinib; D009281:Naphthalenes; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D000068878:Trastuzumab; C572947:1,3-bis((3,4,5-trihydroxybenzoyl)oxy)naphthalene; C401859:temsirolimus; C045651:epigallocatechin gallate; C518729:FASN protein, human; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse; C485206:pertuzumab