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

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.

• Authors: Carlton L Schwab, Diana P English, Jonathan Black, Stefania Bellone, Salvatore Lopez, Emiliano Cocco, Elena Bonazzoli, Beatrice Bussi, Federica Predolini, Francesca Ferrari, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Thomas Rutherford, Peter E Schwartz, Alessandro D Santin
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 139 Issue 1 Pg. 112-7 (Oct 2015) ISSN: 1095-6859 [Electronic] United States
• PMID: 26260909 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Quinolines
• ERBB2 protein, human
• Receptor, ErbB-2
• neratinib

Topics

• Animals
• Carcinosarcoma (drug therapy, enzymology, genetics, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Gene Amplification
• Humans
• Mice
• Mice, SCID
• Ovarian Neoplasms (drug therapy, enzymology, genetics, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Quinolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays