Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo

Carlton L. Schwab, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Diana P. English, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Jonathan Black, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Salvatore Lopez, Division of Gynecologic Oncology, University Campus Biomedico of Roma, Via Álvaro del Portillo, 21-00128 Rome, Italy.
Emiliano Cocco, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Elena Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Beatrice Bussi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Federica Predolini, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Francesca Ferrari, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Elena Ratner, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Dan-Arin Silasi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Masoud Azodi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Thomas Rutherford, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Peter E. Schwartz, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
Alessandro D. Santin, 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.

Document Type

Article

Publication Title

Gynecologic oncology

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.

First Page

112

Last Page

7

DOI

10.1016/j.ygyno.2015.08.002

Publication Date

10-1-2015

Identifier

26260909 (pubmed); NIHMS715306 (mid); PMC4587290 (pmc); 10.1016/j.ygyno.2015.08.002 (doi); S0090-8258(15)30096-2 (pii)

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