Menderes Gulden, Bonazzoli Elena, Bellone Stefania, Black Jonathan D, Lopez Salvatore, Pettinella Francesca, Masserdotti Alice, Zammataro Luca, Litkouhi Babak, Ratner Elena, Silasi Dan-Arin, Azodi Masoud, Schwartz Peter E, Santin Alessandro D
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.
Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome, Italy.
Med Oncol. 2017 May;34(5):91. doi: 10.1007/s12032-017-0956-8. Epub 2017 Apr 10.
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 IC, 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 IC: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.
上皮性卵巢癌是最致命的妇科恶性肿瘤。有必要优化当前可用的治疗策略，并迫切开发针对化疗耐药性疾病的新型治疗药物。我们研究的目的是评估来那替尼在治疗HER2扩增型卵巢癌方面的临床前疗效。利用六种具有不同HER2/neu表达的原发性肿瘤细胞系在体外研究了来那替尼治疗HER2扩增型卵巢癌的疗效。采用流式细胞术评估IC、细胞信号变化和细胞周期分布。在HER2扩增的上皮性卵巢癌异种移植模型中评估了来那替尼的体内疗效。六个卵巢癌细胞系中有三个（50%）HER2/neu扩增。与非HER2/neu扩增的肿瘤细胞系相比，来那替尼在治疗HER2/neu扩增的细胞系时显示出显著更高的疗效（平均±SEM IC：0.010μM±0.0003对0.076μM±0.005，p<0.0001）。来那替尼治疗显著降低了转录因子S6的磷酸化，导致细胞周期停滞在G0/G1期。来那替尼延长了携带HER2扩增上皮性卵巢癌异种移植瘤的小鼠的生存期（p=0.003）。来那替尼在体外抑制HER2扩增上皮性卵巢癌的增殖、信号传导、细胞周期进程和肿瘤生长。来那替尼在体内抑制HER2/neu扩增型卵巢癌的异种移植瘤生长并提高总生存期。有必要进行临床试验。
