A Novel EGFR Extracellular Domain Mutant, EGFRΔ768, Possesses Distinct Biological and Biochemical Properties in Neuroblastoma.
A Novel EGFR Extracellular Domain Mutant, EGFRΔ768, Possesses Distinct Biological and Biochemical Properties in Neuroblastoma.
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DOI：
10.1158/1541-7786.mcr-15-0477
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Chan EL
中科院分区：
文献类型：
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作者：
Keller J;Nimnual AS;Varghese MS;VanHeyst KA;Hayman MJ;Chan EL
表皮生长因子受体（EGFR）是许多癌症的常用治疗靶点。EGFR抑制剂已在难治性神经母细胞瘤（NB）儿童中进行了测试。有趣的是，在少数NB患者中观察到部分缓解或病情稳定。由于EGFR突变是对抗EGFR药物应答的生物标志物，因此筛选原发性NB肿瘤和细胞系的突变。发现了一种新的EGFR胞外结构域缺失突变体EGFRΔ768，并表征了该突变体的生物学和生化特性，并与野生型和EGFRvIII受体进行了比较。发现EGFRΔ768具有组成型活性并定位于细胞表面。它的表达赋予了对依托泊苷的抗性，并驱动癌细胞的增殖和侵袭。虽然EGFRΔ768与EGFRvIII具有相似性，但其生物学和生物化学性质与EGFRvIII和野生型受体明显不同。尽管厄洛替尼抑制EGFRΔ768，但其对突变体的作用不如对野生型EGFR和EGFRvIII的作用强。此外，EGFRΔ768的下游信号传导不同于野生型受体。总之，这是第一项证明神经母细胞瘤不仅表达EGFRvIII，而且表达一种新的EGFR胞外结构域缺失突变体EGFRΔ768的研究。EGFRΔ768还具有独特的生物学和生化特性，可能对神经母细胞瘤以及表达这种新突变体的其他肿瘤具有治疗意义。
Epidermal growth factor receptor (EGFR) is a popular therapeutic target for many cancers. EGFR inhibitors have been tested in children with refractory neuroblastoma (NB). Interestingly, partial response or stable disease was observed in a few NB patients. Since EGFR mutations are biomarkers for response to anti-EGFR drugs, primary NB tumors and cell lines were screened for mutations. A novel EGFR extracellular domain deletion mutant, EGFRΔ768, was discovered and the biological and biochemical properties of this mutant were characterized and compared to wild type and EGFRvIII receptors. EGFRΔ768 was found to be constitutively active and localized to the cell surface. Its expression conferred resistance to etoposide and drove proliferation as well as invasion of cancer cells. While EGFRΔ768 had similarity to EGFRvIII, its biological and biochemical properties were distinctly different from both the EGFRvIII and wild type receptors. Even though erlotinib inhibited EGFRΔ768, its effect on the mutant was not as strong as that on wild type EGFR and EGFRvIII. In addition, downstream signaling of EGFRΔ768 was different from that of the wild type receptor. In conclusion, this is the first study to demonstrate that neuroblastoma express not only EGFRvIII, but also a novel EGFR extracellular domain deletion mutant, EGFRΔ768. The EGFRΔ768 also possesses distinct biological and biochemical properties which might have therapeutic implications for neuroblastoma as well as other tumors expressing this novel mutant.