title: Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo.
abstract: Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib's preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC50, cell signaling changes, and cell cycle distribution. Neratinib's in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC50:0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Gulden
authors.initials: G
authors.lastname: Menderes
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonazzoli
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Black
authors.affiliation: Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lopez
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pettinella
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Masserdotti
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Zammataro
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Litkouhi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ratner
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Dan-Arin
authors.initials: DA
authors.lastname: Silasi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA. alessandro.santin@yale.edu.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000368:Aged; D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C487932:neratinib
keywords: Epithelial ovarian carcinoma; HER2/neu; Neratinib; SCID mice