Therapeutic potential of the dual EGFR/HER2 inhibitor AZD8931 in circumventing endocrine resistance.
Therapeutic potential of the dual EGFR/HER2 inhibitor AZD8931 in circumventing endocrine resistance.
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DOI：
10.1007/s10549-014-2878-x
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发表时间：
2014-04
影响因子：
3.8
通讯作者：
Schiff, Rachel
中科院分区：
文献类型：
--
作者：
Morrison, Gladys;Fu, Xiaoyong;Shea, Martin;Nanda, Sarmistha;Giuliano, Mario;Wang, Tao;Klinowska, Teresa;Osborne, C. Kent;Rimawi, Mothaffar F.;Schiff, Rachel
关键词：
HER-配体或受体的适度上调与获得性内分泌抗性有关。AZD 8931是一种上皮生长因子受体（EGFR）/HER 2的双重酪氨酸激酶抑制剂（TKI），已被证明比HER TKI拉帕替尼或吉非替尼更有效地阻断配体依赖性HER信号传导。因此，我们研究了AZD 8931在ER阳性/HER 2阴性乳腺癌细胞中的作用，这些细胞对他莫昔芬具有获得性耐药，其中配体上调与HER途径激活相关。在ER+ MCF 7和T47 D亲本细胞及其TAM抗性衍生物（TamRes）中进行RNA-seq配体分析和HER受体水平以及通过蛋白质印迹的信号传导。在体外细胞生长和细胞凋亡和HER配体刺激的信号转导进行了测量，以响应内分泌和HER TKI。对于体内研究，用他莫昔芬或氟维司群单独或与AZD 8931组合处理可移植的MCF 7/TamRes异种移植物。AZD 8931仅极轻微地增强了MCF 7亲本细胞的内分泌敏感性，但在T47 D亲本模型中显示出更大的作用。在T47 D TamRes细胞中，AZD 8931联合他莫昔芬或氟维司群对细胞生长的抑制作用大于拉帕替尼，在MCF 7 TamRes细胞中也显著（尽管适度）更有效。在两种TamRes模型中，AZD 8931均显著抑制细胞增殖并诱导细胞凋亡。在配体刺激条件下，AZD 8931比拉帕替尼或吉非替尼更有效地抑制HER信号传导。在他莫昔芬或氟维司群存在下，AZD 8931还显著延迟了MCF 7 TamRes异种移植物的生长。氟维司群和AZD 8931组合实现了最强的抑制，尽管没有观察到肿瘤消退。这项研究提供的证据表明，AZD 8931在他莫昔芬耐药环境中的抑制疗效高于内分泌治疗初治环境。然而，肿瘤消退的缺乏表明，额外的逃逸途径有助于耐药生长，需要有针对性地完全规避他莫昔芬耐药。
Modest up-regulation of either HER-ligands or receptors has been implicated in acquired endocrine resistance. AZD8931, a dual tyrosine kinase inhibitor (TKI) of epithelial growth factor receptor (EGFR)/HER2, has been shown to more effectively block ligand-dependent HER signaling than the HER TKIs lapatinib or gefitinib. We therefore examined the effect of AZD8931 in ER-positive/HER2-negative breast cancer cells with acquired resistance to tamoxifen, where there is ligand up-regulation associated with HER pathway activation. RNA-seq ligand profiling and levels of HER receptors and signaling by western blotting were conducted in ER+ MCF7 and T47D parental cells and their Tam-resistant derivatives (TamRes). In vitro cell growth and apoptosis and HER ligand-stimulated signaling were measured in response to endocrine and HER TKIs. For studies in vivo, transplantable MCF7/TamRes xenografts were treated with tamoxifen or fulvestrant, either alone or in combination with AZD8931. AZD8931 only minimally enhanced endocrine sensitivity in MCF7 parental cells, but showed a greater effect in the T47D parental model. AZD8931 combined with either tamoxifen or fulvestrant inhibited cell growth more than lapatinib in T47D TamRes cells, and was also significantly, though modestly, more potent in MCF7 TamRes cells. In both TamRes models, AZD8931 significantly inhibited cell proliferation and induced apoptosis. Under ligand-stimulated conditions, AZD8931 more potently inhibited HER signaling than lapatinib or gefitinib. AZD8931 also significantly delayed the growth of MCF7 TamRes xenografts in the presence of tamoxifen or fulvestrant. The strongest inhibition was achieved with a fulvestrant and AZD8931 combination, though no tumor regression was observed. This study provides evidence that AZD8931 has greater inhibitory efficacy in tamoxifen-resistant settings than in an endocrine therapy naïve setting. The absence of tumor regression, however, suggests that additional escape pathways contribute to resistant growth and will need to be targeted to fully circumvent tamoxifen resistance.
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影响因子：
11.5
作者：
Cristofanilli, Massimo;Valero, Vicente;Magill, Patrick J.
通讯作者：
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影响因子：
11.5
作者：
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影响因子：
45.3
作者：
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影响因子：
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作者：
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Lykkesfeldt, Anne E.
DOI：
10.1016/j.jsbmb.2007.05.019
发表时间：
2007-08-01
影响因子：
4.1
作者：
Johnston, Stephen R. D.;Martin, Lesley-Ann;Dowsett, Mitch
通讯作者：
Dowsett, Mitch