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Gynecol Oncol. 2015 Oct;139(1):112-7. doi: 10.1016/j.ygyno.2015.08.002. Epub 2015 Aug 8.

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

Author information

1
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street New Haven, CT 06520, United States.
2
Division of Gynecologic Oncology, University Campus Biomedico of Roma, Via Álvaro del Portillo, 21-00128 Rome, Italy.
3
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.

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.

KEYWORDS:

Carcinosarcoma; ErbB2; HER2/neu; TKI; Targeted therapy

PMID:
26260909
PMCID:
PMC4587290
DOI:
10.1016/j.ygyno.2015.08.002
[Indexed for MEDLINE]
Free PMC Article

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