MEK Inhibitor Selumetinib (AZD6244; ARRY-142886) Prevents Lung Metastasis in a Triple-Negative Breast Cancer Xenograft Model.
MEK Inhibitor Selumetinib (AZD6244; ARRY-142886) Prevents Lung Metastasis in a Triple-Negative Breast Cancer Xenograft Model.
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DOI：
10.1158/1535-7163.mct-15-0243
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发表时间：
2015-12
影响因子：
5.7
通讯作者：
Ueno NT
中科院分区：
文献类型：
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作者：
Bartholomeusz C;Xie X;Pitner MK;Kondo K;Dadbin A;Lee J;Saso H;Smith PD;Dalby KN;Ueno NT
三阴性乳腺癌（TNBC）患者预后不良，因为TNBC经常转移，导致死亡。在TNBC患者中，ERK 2（细胞外信号调节激酶2）过表达肿瘤患者的死亡风险高于ERK 2低表达肿瘤患者（风险比，2.76; 95%置信区间，1.19-6.41）。MAPK通路已被证明是乳腺癌转移的标志物，但尚未被探索为预防TNBC转移的潜在治疗靶点。有趣的是，当我们用别构MEK抑制剂司美替尼处理TNBC细胞时，细胞活力在二维培养中没有降低。然而，在三维培养中，司美替尼将TNBC细胞的间充质表型改变为上皮表型。经历上皮-间充质转化（EMT）的细胞被认为有助于转移过程。EMT导致产生具有干细胞样特征和CD 44 + CD 24 −/低表达模式的间充质样乳腺癌细胞。我们检验了司美替尼靶向抑制MAPK通路抑制乳腺癌干细胞表型获得并预防TNBC肺转移的假设。用司美替尼处理的TNBC细胞显示出对锚定非依赖性生长的抑制，这是体内致瘤性的一个指标（P<0.005），并且CD 44 + CD 24 −/低分数、ALDH 1活性和乳腺球形成效率降低。用司美替尼治疗的小鼠形成的肺转移显著少于用媒介物注射的对照小鼠（P<0.05）。我们的数据表明，MEK抑制剂可以抑制乳腺癌干细胞，并可能具有预防转移的临床潜力，以防止肿瘤依赖MAPK的某些情况下的转移。
Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with ERK2 (extracellular signal-regulated kinase 2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19–6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK inhibitor selumetinib, cell viability was not reduced in 2-dimensional culture. However, in 3-dimensional culture, selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44+CD24−/low expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P<0.005), and decreases in the CD44+CD24−/low fraction, ALDH1 activity and mammosphere-forming efficiency. Mice treated with selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P<0.05). Our data demonstrate that MEK inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis to prevent metastasis in certain cases in which tumors are MAPK dependent.