title: Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.
abstract: OBJECTIVE
  Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts.
  
  
  METHODS
  Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation.
  
  
  RESULTS
  HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation.
  
  
  CONCLUSIONS
  Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.|Harvard Medical School, Boston, MA, United States.
authors.forename: Jolijn W
authors.initials: JW
authors.lastname: Groeneweg
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.|Harvard Medical School, Boston, MA, United States.
authors.forename: Silvia F
authors.initials: SF
authors.lastname: Hernandez
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Virginia F
authors.initials: VF
authors.lastname: Byron
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: DiGloria
authors.affiliation: Department of Medicine, Cancer Center, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Hector
authors.initials: H
authors.lastname: Lopez
authors.affiliation: Department of Medicine, Cancer Center, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Scialabba
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Minji
authors.initials: M
authors.lastname: Kim
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Cancer Center, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.affiliation: Harvard Medical School, Boston, MA, United States.|Department of Pathology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Tambouret
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.|Harvard Medical School, Boston, MA, United States.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.|Harvard Medical School, Boston, MA, United States.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.|Harvard Medical School, Boston, MA, United States.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005784:Gene Amplification / Q000187:drug effects*; D015870:Gene Expression; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab