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Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo.
- Source :
-
Gynecologic oncology [Gynecol Oncol] 2015 Oct; Vol. 139 (1), pp. 112-7. Date of Electronic Publication: 2015 Aug 08. - Publication Year :
- 2015
-
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.<br />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.<br />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).<br />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.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Carcinosarcoma enzymology
Carcinosarcoma genetics
Carcinosarcoma pathology
Cell Cycle drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Female
Gene Amplification
Humans
Mice
Mice, SCID
Ovarian Neoplasms enzymology
Ovarian Neoplasms genetics
Ovarian Neoplasms pathology
Receptor, ErbB-2 genetics
Receptor, ErbB-2 metabolism
Xenograft Model Antitumor Assays
Carcinosarcoma drug therapy
Ovarian Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Quinolines pharmacology
Receptor, ErbB-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1095-6859
- Volume :
- 139
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gynecologic oncology
- Publication Type :
- Academic Journal
- Accession number :
- 26260909
- Full Text :
- https://doi.org/10.1016/j.ygyno.2015.08.002