Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo

Gulden Menderes, 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.
Elena Bonazzoli, 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.
Stefania Bellone, 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.
Jonathan D. Black, 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.
Salvatore Lopez, Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome, Italy.
Francesca Pettinella, 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.
Alice Masserdotti, 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.
Luca Zammataro, 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.
Babak Litkouhi, 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.
Elena Ratner, 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.
Dan-Arin Silasi, 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.
Masoud Azodi, 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.Follow
Peter E. Schwartz, 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 D. Santin, 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.

Document Type

Article

Publication Title

Medical oncology (Northwood, London, England)

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 IC, 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 IC: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.

First Page

91

DOI

10.1007/s12032-017-0956-8

Publication Date

5-1-2017

Identifier

28397106 (pubmed); NIHMS957062 (mid); PMC5896014 (pmc); 10.1007/s12032-017-0956-8 (doi); 10.1007/s12032-017-0956-8 (pii)

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