EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy
EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy
复制标题
DOI：
10.1215/15228517-2008-053
复制
发表时间：
2008-12-01
期刊：
影响因子：
15.9
通讯作者：
von Deimling, Andreas
中科院分区：
文献类型：
--
作者：
Holtkamp, Nikola;Malzer, Elke;von Deimling, Andreas
恶性周围神经鞘瘤（MPNST）是一种预后不良且治疗选择有限的肉瘤。表皮生长因子受体（EGFR）和受体酪氨酸激酶erbB 2在MPNSTs中的作用的证据使我们在更大的肿瘤组（n=37）中系统地研究这些潜在的治疗靶点。多重连接依赖性探针扩增和荧光原位杂交分析显示，28%的MPNST中EGFR剂量增加。ERBB 2和三种肿瘤抑制基因（PTEN [10号染色体上缺失的磷酸酶和张力蛋白同源物]、CDKN 2A [细胞周期蛋白依赖性激酶抑制剂2A]和TP 53 [肿瘤蛋白p53]）经常丢失或减少。CDKN 2A的减少与转移的出现有关。相应的神经纤维瘤和MPNST的比较显示，MPNST的遗传病变增加。EGFR和ERBB 2的酪氨酸激酶编码外显子内未发现体细胞突变。然而，在蛋白水平，EGFR和erbB 2的表达频繁检测MPNST。EGFR表达与EGFR基因剂量增加显著相关。EGFR配体、转化生长因子α和EGF在MPNST中的表达强于神经纤维瘤。在MPNST细胞系上测定了靶向EGFR和erbB 2的药物厄洛替尼和曲妥珠单抗的作用。与曲妥珠单抗相反，厄洛替尼介导的细胞增殖抑制呈剂量依赖性。EGF诱导的EGFR磷酸化被厄洛替尼减弱。总之，我们的数据表明，EGFR和erbB 2是治疗MPNST患者的潜在靶点。Neuro-Oncology 10，946-957，2008（Posted to Neuro-Oncology [serial online]，Doc. D 07 -00250，2008年7月23日。网址http://neuro-oncology.dukejournals.org; DOI：10.1215/15228517-2008-053）
Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n=37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor a and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients. Neuro-Oncology 10, 946-957, 2008 (Posted to Neuro-Oncology [serial online], Doc. D07-00250, July 23, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-053)