A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells
A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells
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DOI：
10.1038/onc.2014.351
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发表时间：
2015-08-06
期刊：
影响因子：
8
通讯作者：
Yde, C. W.
中科院分区：
文献类型：
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作者：
Thrane, S.;Pedersen, A. M.;Yde, C. W.
抗雌激素抵抗是乳腺癌治疗中的一个主要问题。因此，寻找新的抗雌激素抵抗的治疗靶点和生物标志物至关重要。在这项研究中，我们进行了激酶抑制剂筛选抗雌激素反应的MCF-7细胞和一组MCF-7衍生的他莫昔芬和氟维司群耐药细胞系。我们的重点是确定共同的和不同的分子机制参与他莫昔芬和氟维司群耐药细胞生长。我们确定了18种抑制剂，其中大多数是常见的他莫昔芬和氟维司群耐药细胞系。选择对抗雌激素耐药细胞系表现出显著优先生长抑制作用的两种化合物WP 1130和JNJ-7706621进行进一步研究。WP 1130是一种去遍在蛋白酶抑制剂，通过使抗凋亡蛋白Mcl-1不稳定，在他莫昔芬和氟维司群耐药细胞系中诱导半胱天冬酶介导的细胞死亡。Mcl-1的表达被发现在抗雌激素抗性细胞系中上调，并且抗性细胞中Mcl-1的耗尽导致活力降低。JNJ-7706621是一种双重Aurora激酶和细胞周期蛋白依赖性激酶抑制剂，可特异性抑制他莫昔芬耐药细胞系的生长并导致G2期细胞周期停滞。敲除研究表明，Aurora激酶A对于他莫昔芬耐药细胞的生长和抑制Aurora激酶A使他莫昔芬耐药细胞对他莫昔芬治疗重新敏感是必需的。在T47 D衍生的他莫昔芬耐药细胞系中也发现了WP 1130和JNJ-7706621的优先生长抑制作用，表明Mcl-1和Aurora激酶A是潜在的治疗靶点。此外，来自244例接受他莫昔芬辅助治疗的雌激素受体阳性乳腺癌患者的肿瘤样本显示，Aurora激酶A的表达水平较高与无病生存期和总生存期较短显著相关，证明Aurora激酶A作为他莫昔芬耐药生物标志物的潜力。
Antiestrogen resistance is a major problem in breast cancer treatment. Therefore, the search for new therapeutic targets and biomarkers for antiestrogen resistance is crucial. In this study, we performed a kinase inhibitor screen on antiestrogen responsive MCF-7 cells and a panel of MCF-7-derived tamoxifen- and fulvestrant-resistant cell lines. Our focus was to identify common and distinct molecular mechanisms involved in tamoxifen- and fulvestrant-resistant cell growth. We identified 18 inhibitors, of which the majority was common for both tamoxifen- and fulvestrant-resistant cell lines. Two compounds, WP1130 and JNJ-7706621, exhibiting prominent preferential growth inhibition of antiestrogen-resistant cell lines, were selected for further studies. WP1130, a deubiquitinase inhibitor, induced caspase-mediated cell death in both tamoxifen- and fulvestrant-resistant cell lines by destabilization of the anti-apoptotic protein Mcl-1. Mcl-1 expression was found upregulated in the antiestrogen-resistant cell lines and depletion of Mcl-1 in resistant cells caused decreased viability. JNJ-7706621, a dual Aurora kinase and cyclin-dependent kinase inhibitor, specifically inhibited growth and caused G2 phase cell cycle arrest of the tamoxifen-resistant cell lines. Knockdown studies showed that Aurora kinase A is essential for growth of the tamoxifen-resistant cells and inhibition of Aurora kinase A resensitized tamoxifen-resistant cells to tamoxifen treatment. Preferential growth inhibition by WP1130 and JNJ-7706621 was also found in T47D-derived tamoxifen-resistant cell lines, pointing at Mcl-1 and Aurora kinase A as potential treatment targets. In addition, tumor samples from 244 estrogen receptor-positive breast cancer patients treated with adjuvant tamoxifen showed that higher expression level of Aurora kinase A was significantly associated with shorter disease-free and overall survival, demonstrating the potential of Aurora kinase A as a biomarker for tamoxifen resistance.