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

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.

Anti‑tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations

“…Two HER2 -amplified (H2170 and Calu-3) cell lines and one HER2 -mutant (H1781) cell line were used for this experiment. The dose of neratinib was selected based on the results of previous reports (29,30). Once the xenograft tumor volume reached ~50 mm 3 , the mice were orally treated with the vehicle alone or neratinib (40 mg⁄kg, 6 days a week).…”

PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers

“…Our data revealing PIK3CA mutations as one of the main mechanisms of resistance to afatinib combined with the high percentage of USC patients known to potentially harbor such mutations in their tumors [21], may potentially explain the common resistance of these tumors to anti-HER2/neu treatment when used as single agent. Importantly, the encouraging experimental results obtained with afatinib or neratinib (ie, another pan c-erb inhibitor) when used in combinations with PIK3CA inhibitors [37] allow the speculation that targeting of the HER2/PI3K/AKT/mTOR pathway with afatinib in combination with PIK3CA, AKT or mTOR inhibitors, may represent a more effective and more durable treatment modality in patients harboring HER2-amplified and PIK3CA mutated tumors [38][39][40].…”

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence

“…223 Thus, EGFR and HER2 are promising targets for treatment of cancer. [224][225][226][227] HER-targeted drugs include monoclonal antibodies and smallmolecule inhibitors. Monoclonal antibodies against the extracellular domain of the HER receptor include cetuximab, nimotuzumab, trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1).…”