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

• This is the first evaluation of the efficacy of neratinib in ovarian and uterine carcinosarcomas.
• Neratinib may represent a novel therapeutic agent for ovarian and uterine carcinosarcomas.
• HER2 amplification determines sensitivity of ovarian and uterine carcinosarcomas to neratinib.

ObjectiveCarcinosarcoma 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.MethodsThe 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.ResultsTwo 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 IC50:0.014 μM ± 0.004vs.0.164 μM ± 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).ConclusionsNeratinib 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.