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Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo

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Abstract

Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib’s preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib’s efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC50, cell signaling changes, and cell cycle distribution. Neratinib’s in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC50:0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.

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Funding

This work was supported in part by R01 CA154460-01 and U01 CA176067-01A1 grants from NIH, and grants from the Deborah Bunn Alley Foundation, the Tina Brozman Foundation, the Discovery to Cure Foundation and the Guido Berlucchi Foundation to A.D. Santin. This investigation was also supported by NIH Research Grant CA-16359 from the NCI to A.D. Santin.

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA

    Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan D. Black, Francesca Pettinella, Alice Masserdotti, Luca Zammataro, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E. Schwartz & Alessandro D. Santin

  2. Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome, Italy

    Salvatore Lopez

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  1. Gulden Menderes
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  2. Elena Bonazzoli
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Correspondence to Alessandro D. Santin.

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All applicable international, national, and/or institutional guidelines for the care and use of mice were followed. Ethical approval for involving mice in our study was obtained from Yale Institutional Animal Care and Use Committee (IACUC) which granted the ethical approval after review. The policies set forth by the IACUC at Yale University were followed while housing and treating the mice.

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Menderes, G., Bonazzoli, E., Bellone, S. et al. Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo. Med Oncol 34, 91 (2017). https://doi.org/10.1007/s12032-017-0956-8

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