Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Division of Gynecologic Oncology, University Campus Biomedico of Roma, Via Álvaro del Portillo, 21-00128 Roma, Rome, Italy.
Gynecol Oncol. 2014 Oct;135(1):142-8. doi: 10.1016/j.ygyno.2014.08.006. Epub 2014 Aug 12.
Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associated with USC in approximately 30-35% of cases. The objective of this study was to determine the sensitivity of a panel of primary USC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo.
HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro. Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo.
HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC50: 0.011μM ± 0.0008 vs. 0.312μM ± 0.0456 p<0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p=0.0019).
Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.
子宫浆液性癌（USC）是子宫内膜癌的一种侵袭性变异，占每年死亡人数的很大比例。约 30-35%的病例存在 HER2/neu 扩增。本研究的目的是确定一组原发性 USC 细胞系对小分子酪氨酸激酶抑制剂奈拉替尼（一种 ErbB1 和 HER2 抑制剂）的体外和体内敏感性。
通过免疫组织化学（IHC）和荧光原位杂交（FISH）检测 24 个 USC 细胞系中 HER2/neu 的扩增。流式细胞术用于确定奈拉替尼对细胞活力、细胞周期分布和信号转导的影响。携带 HER2/neu 扩增异种移植物的小鼠用奈拉替尼治疗，以评估药物在体内的疗效。
在 24 个原发性细胞系中，HER2/neu 扩增。使用 4 个 HER2 扩增细胞系和 4 个生长速度相似的非扩增细胞系确定了奈拉替尼的疗效数据。数据显示，HER2/neu 扩增的细胞系对奈拉替尼的敏感性明显高于非扩增细胞系（平均±SEM IC50：0.011μM±0.0008 与 0.312μM±0.0456，p<0.0001）。奈拉替尼导致细胞周期 G0/G1 期停滞，并导致 HER2 的自身磷酸化减少和 S6 的激活。与载体相比，用奈拉替尼治疗携带 HER2/neu 扩增 USC 异种移植物的小鼠显示出肿瘤生长延迟和总生存期改善（p=0.0019）。
奈拉替尼可能是携带 HER2/neu 扩增 USC 的患者的潜在治疗选择。需要对这部分子宫内膜癌患者进行临床试验。
