title: Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo.
abstract: OBJECTIVE
  Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma.
  
  
  METHODS
  The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC50, cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts.
  
  
  RESULTS
  Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50:0.014μM±0.004vs.0.164μM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039).
  
  
  CONCLUSIONS
  Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Carlton L
authors.initials: CL
authors.lastname: Schwab
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Diana P
authors.initials: DP
authors.lastname: English
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Division of Gynecologic Oncology, University Campus Biomedico of Roma, Via Álvaro del Portillo, 21-00128 Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lopez
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonazzoli
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bussi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Federica
authors.initials: F
authors.lastname: Predolini
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Elena
authors.initials: E
authors.lastname: Ratner
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Dan-Arin
authors.initials: DA
authors.lastname: Silasi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rutherford
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States. Electronic address: Alessandro.santin@yale.edu.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000818:Animals; D002296:Carcinosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C487932:neratinib
keywords: Carcinosarcoma; ErbB2; HER2/neu; TKI; Targeted therapy