AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer
AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer
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DOI：
10.1158/1078-0432.ccr-09-2353
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发表时间：
2010-02-15
影响因子：
11.5
通讯作者：
Ogilvie, Donald
中科院分区：
文献类型：
--
作者：
Hickinson, D. Mark;Klinowska, Teresa;Ogilvie, Donald
目的：验证新型小分子抑制剂AZD8931同时等效抑制表皮生长因子受体（EGFR; erbB1）、erbB2（人表皮生长因子受体2）和erbB3受体信号传导，在体内和体外具有广泛的抗肿瘤活性的假设。实验设计：采用一系列的分析方法来模拟erbB家族受体在同二聚体和异二聚体中的信号传导，包括erbB激酶活性的体外评估、erbB受体磷酸化、细胞增殖、人类肿瘤异种移植组的体内测试，以及erbB磷酸化和下游生物标志物的体外评估。使用吉非替尼和拉帕替尼比较AZD8931与其他erbB家族抑制剂的药理学特征。结果：AZD8931在体外对细胞中EGFR （IC50, 4 nmol/L）、erbB2 （IC50, 3 nmol/L）和erbB3 （IC50, 4 nmol/L）磷酸化具有等效、可逆的抑制作用。在增殖试验中，AZD8931对头颈部特异性鳞状细胞癌和非小细胞肺癌细胞系的效力明显高于吉非替尼或拉帕替尼。在体内，AZD8931在一系列模型中抑制异种移植物生长，同时显著影响EGFR、erbB2和erbB3磷酸化和下游信号通路、细胞凋亡和增殖。结论：AZD8931具有独特的药理学特征，对EGFR、erbB2和erbB3信号通路具有同等的抑制作用，在特定的临床前模型中，与erbB受体抑制谱较窄的药物相比，AZD8931具有更强的抗肿瘤活性。AZD8931提供了研究同时抑制erbB受体信号传导是否在临床中有用的机会，特别是在大多数不过度表达erbB2的实体肿瘤中。临床癌症研究；16 (4);1159 - 69。(c) 2010年aacr。
Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo.Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors.Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC50, 4 nmol/L), erbB2 (IC50, 3 nmol/L), and erbB3 (IC50, 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159-69. (C) 2010 AACR.