Glioblastoma-Derived Epidermal Growth Factor Receptor Carboxyl-Terminal Deletion Mutants Are Transforming and Are Sensitive to EGFR-Directed Therapies
Glioblastoma-Derived Epidermal Growth Factor Receptor Carboxyl-Terminal Deletion Mutants Are Transforming and Are Sensitive to EGFR-Directed Therapies
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DOI：
10.1158/0008-5472.can-11-0821
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Meyerson, Matthew
中科院分区：
文献类型：
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作者：
Cho, Jeonghee;Pastorino, Sandra;Meyerson, Matthew
表皮生长因子受体（EGFR）基因的基因组改变在多形性胶质母细胞瘤（GBM）的发病机制中起关键作用。通过对GBM基因组数据的系统分析，我们已经确定并表征了发生在EGFR羧基末端结构域（CTD）内的一个新的外显子27缺失突变，以及该区域先前报道的其他缺失突变的例子。我们发现gbm衍生的EGFR CTD缺失突变体能够在体外和体内诱导没有配体和受体自磷酸化的细胞转化。用靶向EGFR的单克隆抗体西妥昔单抗或小分子EGFR抑制剂厄洛替尼治疗，有效地削弱了致癌性EGFR CTD缺失突变体的致瘤性。与未治疗的对照组小鼠相比，西妥昔单抗特别延长了带有致癌EGFR CTD缺失突变的颅内异种移植小鼠的存活时间。因此，我们建议厄洛替尼，特别是西妥昔单抗治疗可能是一种有希望的治疗策略，用于携带EGFR CTD缺失突变体的GBM患者。癌症Res;71 (24);7587 - 96。AACR (C) 2011。
Genomic alterations of the epidermal growth factor receptor (EGFR) gene play a crucial role in pathogenesis of glioblastoma multiforme (GBM). By systematic analysis of GBM genomic data, we have identified and characterized a novel exon 27 deletion mutation occurring within the EGFR carboxyl-terminus domain (CTD), in addition to identifying additional examples of previously reported deletion mutations in this region. We show that the GBM-derived EGFR CTD deletion mutants are able to induce cellular transformation in vitro and in vivo in the absence of ligand and receptor autophosphorylation. Treatment with the EGFR-targeted monoclonal antibody, cetuximab, or the small molecule EGFR inhibitor, erlotinib, effectively impaired tumorigenicity of oncogenic EGFR CTD deletion mutants. Cetuximab in particular prolonged the survival of intracranially xenografted mice with oncogenic EGFR CTD deletion mutants, compared with untreated control mice. Therefore, we propose that erlotinib and, especially, cetuximab treatment may be a promising therapeutic strategy in GBM patients harboring EGFR CTD deletion mutants. Cancer Res; 71(24); 7587-96. (C)2011 AACR.