The non-small cell lung cancer EGFR extracellular domain mutation, M277E, is oncogenic and drug-sensitive.
The non-small cell lung cancer EGFR extracellular domain mutation, M277E, is oncogenic and drug-sensitive.
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非小细胞肺癌 EGFR 胞外域突变 M277E 具有致癌性和药物敏感性
DOI：
10.2147/ott.s131999
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发表时间：
2017
影响因子：
4
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Yu S;Zhang Y;Pan Y;Cheng C;Sun Y;Chen H
在已知靶基因缺乏突变的非小细胞肺癌患者标本（“泛阴性”患者）中鉴定新的致癌突变。对1356例肺腺癌标本进行了全面的突变分析。在这组患者中，在表皮生长因子受体（EGFR）激酶结构域、人表皮生长因子受体2激酶结构域以及KRAS、BRAF、ALK、ROS1和RET基因中检测到常见的肺癌致癌驱动突变。对一组泛阴性患者标本进行EGFR细胞外结构域（ECD）突变检测。此外，构建EGFR突变的NIH-3T3稳定细胞系，并在异种移植模型中评估其蛋白质含量、非锚定生长和肿瘤形成，以确定致癌突变。BaF3淋巴细胞也被用来检测突变对酪氨酸激酶抑制剂的敏感性。在泛阴性肺腺癌病例中，发现了一种新的致癌EGFR ECD突变（M277E）。EGFR M277E突变编码癌蛋白，使NIH-3T3细胞在缺乏外源性表皮生长因子的情况下生长。在免疫功能低下的异种移植物小鼠模型中，非锚定生长和肿瘤形成进一步证明了这种转化。最后，在典型的EGFR L858R突变中可以看到，M277E突变使BaF3细胞系对厄洛替尼和西妥昔单抗敏感，并在异种移植模型中对厄洛替尼敏感。这里，在肺腺癌标本的ECD中发现了一种新的EGFR驱动突变M277E。对于经历疾病复发的m277e突变型肺腺癌患者，使用EGFR酪氨酸激酶抑制剂治疗可能预示良好的预后。
To identify novel oncogenic mutations in non-small cell lung cancer patient specimens that lack mutations in known targetable genes (“pan-negative” patients). Comprehensive mutational analyses were performed on 1,356 lung adenocarcinoma specimens. In this cohort of patients, common lung cancer oncogenic driver mutations were detected in the epidermal growth factor receptor (EGFR) kinase domain, the human epidermal growth factor receptor 2 kinase domain, as well as the KRAS, BRAF, ALK, ROS1 and RET genes. A sub-cohort of pan-negative patient specimens was assayed for mutations in the EGFR extracellular domain (ECD). Additionally, EGFR mutant NIH-3T3 stable cell lines were constructed and assessed for protein content, anchorage-independent growth, and tumor formation in xenograft models to identify oncogenic mutations. BaF3 lymphocytes were also used to test sensitivities of the mutations to tyrosine kinase inhibitors. In pan-negative lung adenocarcinoma cases, a novel oncogenic EGFR ECD mutation was identified (M277E). EGFR M277E mutations encoded oncoproteins that transformed NIH-3T3 cells to grow in the absence of exogenous epidermal growth factor. Transformation was further evidenced by anchorage-independent growth and tumor formation in immunocompromised xenograft mouse models. Finally, as seen in the canonical EGFR L858R mutation, the M277E mutation conferred sensitivity to both erlotinib and cetuximab in BaF3 cell lines and to erlotinib in xenograft models. Here, a new EGFR driver mutation, M277E, was identified in the ECD of a lung adenocarcinoma specimen. For patients with M277E-mutant lung adenocarcinoma who experienced disease recurrence, treatment with an EGFR tyrosine kinase inhibitor may predict good prognosis.