Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain.
Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain.
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拉帕替尼对转移性乳腺癌细胞生长到大脑的影响。
DOI：
10.1093/jnci/djn216
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发表时间：
2008-08-06
影响因子：
10.3
通讯作者：
Steeg, Patricia S.
中科院分区：
文献类型：
--
作者：
Gril, Brunilde;Palmieri, Diane;Bronder, Julie L.;Herring, Jeanne M.;Vega-Valle, Eleazar;Feigenbaum, Lionel;Liewehr, David J.;Steinberg, Seth M.;Merino, Maria J.;Rubin, Stephen D.;Steeg, Patricia S.
在接受曲妥珠单抗治疗的HER2过表达乳腺癌患者中，大脑越来越被认为是转移肿瘤细胞的避难所。除了类固醇、头颅放射治疗和手术切除外，还没有被批准或被广泛接受的脑转移瘤治疗方法。我们检测了拉帕替尼，一种表皮生长因子受体(EGFR)和HER2激酶的抑制剂，在小鼠脑转移的异种移植模型中防止乳腺癌细胞在脑内生长的有效性。将EGFR高表达的MDA-MB-231-BR(231-BR)基因导入含或不含HER2基因的乳腺癌细胞，通过免疫印迹法检测拉帕替尼对细胞信号蛋白活化(即磷酸化)的影响，通过四唑盐3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴化法和Boyden小室实验检测拉帕替尼对细胞生长和迁移的影响。将231-BR细胞注入裸小鼠左室，5天后开始用拉帕替尼或赋形剂灌胃(n=22~26只/组)，在裸鼠脑切片上计数大(即50µm~2)和微转移瘤的生长情况。所有的统计检验都是双面的。在体外，拉帕替尼抑制EGFR、HER2和下游信号蛋白的磷酸化，抑制细胞增殖和在231-BR细胞中的迁移(无论有没有HER2)。在注射231-BR载体细胞的小鼠中，开始治疗24天后，100 mg/kg体重组的大转移瘤比赋形剂组少54%(平均每脑切片大转移数：1.56比3.36，差异=1.80，95%可信区间[CI]=0.92~2.68，P<；.001)，而30 mg/kg体重组没有影响。在注射231-BR-HER2细胞的小鼠中，两种剂量的拉帕替尼治疗组的大转移率都比赋形剂组少50%-53%(每个脑切片的平均大转移瘤数，30 mg/kg与赋形剂组：3.21比6.83，差异=3.62，95%CI=2.30~4.94，P<；.001；100 mg/kg与赋形剂组：3.44比6.83，差值=3.39，95%CI=2.08~4.70，P<；.001)。免疫组织化学分析显示，与赋形剂治疗的小鼠的231-BR-HER2细胞来源的脑转移瘤相比，高剂量拉帕替尼治疗的小鼠的231-BR-HER2细胞来源的脑转移瘤中HER2的磷酸化水平降低(P<；.001)。拉帕替尼是第一个在临床前模型中证实具有抗乳腺癌脑转移活性的HER2导向药物。
The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis. EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting, on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and on cell migration using a Boyden chamber assay. The outgrowth of large (ie, >50 µm2) and micrometastases was counted in brain sections from nude mice that had been injected into the left cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapatinib or vehicle (n = 22-26 mice per treatment group). All statistical tests were two-sided. In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in 231-BR cells (both with and without HER2). Among mice injected with 231-BR-vector cells, those treated with 100 mg lapatinib/kg body weight had 54% fewer large metastases 24 days after starting treatment than those treated with vehicle (mean number of large metastases per brain section: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to 2.68, P < .001), whereas treatment with 30 mg lapatinib/kg body weight had no effect. Among mice injected with 231-BR-HER2 cells, those treated with either dose of lapatinib had 50%-53% fewer large metastases than those treated with vehicle (mean number of large metastases per brain section, 30 mg/kg vs vehicle: 3.21 vs 6.83, difference = 3.62, 95% CI = 2.30 to 4.94, P < .001; 100 mg/kg vs vehicle: 3.44 vs 6.83, difference = 3.39, 95% CI = 2.08 to 4.70, P < .001). Immunohistochemical analysis revealed reduced phosphorylation of HER2 in 231-BR-HER2 cell-derived brain metastases from mice treated with the higher dose of lapatinib compared with 231-BR-HER2 cell-derived brain metastases from vehicle-treated mice (P < .001). Lapatinib is the first HER2-directed drug to be validated in a preclinical model for activity against brain metastases of breast cancer.
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