ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells.
ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells.
复制标题
DOI：
--
复制
发表时间：
2003-04
期刊：
影响因子：
--
通讯作者：
J. Anido;P. Matar;J. Albanell;M. Guzman;F. Rojo;J. Arribas;S. Averbuch;J. Baselga
中科院分区：
文献类型：
--
作者：
J. Anido;P. Matar;J. Albanell;M. Guzman;F. Rojo;J. Arribas;S. Averbuch;J. Baselga
ZD 1839是一种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，对EGFR表达肿瘤具有临床活性。我们的目的是探索ZD 1839在表达不同水平EGFR和密切相关的HER 2受体的乳腺癌细胞系中的作用。实验设计我们研究了ZD 1839在一系列乳腺癌细胞系中的生长抑制作用。在HER 2过表达的BT-474乳腺癌细胞中，我们研究了ZD 1839在基础和配体刺激条件下对细胞生长和受体异源二聚化的影响。结果ZD 1839对高表达EGFR和HER 2的乳腺癌细胞的生长具有同等效力的抑制作用。在BT-474乳腺癌细胞中，ZD 1839消除了EGF和heregulin诱导的ErbB受体和下游信号分子的激活。因为ZD 1839在体外不抑制HER 2酪氨酸激酶，并且因为heregulin是通过结合HER 3和HER 4激活HER 2但不结合EGFR的配体，所以我们的研究结果表明ZD 1839干扰完整细胞中的HER 2功能。寻找机制，我们报告ZD 1839诱导形成无活性的非磷酸化EGFR/HER 2和EGFR/HER 3异二聚体。此外，ZD 1839完全消除了基础和调蛋白诱导的活性磷酸化HER 2/HER 3异二聚体的形成。结论：ZD 1839可抑制HER 2过表达乳腺癌细胞的生长，可能是通过与EGFR以非活性异源二聚体构型隔离HER 2和HER 3受体。我们的研究结果表明，在HER 2过表达乳腺肿瘤患者中进行ZD 1839临床试验有很强的理由。
PURPOSE ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. EXPERIMENTAL DESIGN We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. RESULTS ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro, and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. CONCLUSIONS ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors.