<br>EGFRvIII 上调 DNA 错配修复，导致 MGMT 启动子甲基化胶质母细胞瘤的替莫唑胺敏感性增加。,Oncogene

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EGFRvIII 上调 DNA 错配修复，导致 MGMT 启动子甲基化胶质母细胞瘤的替莫唑胺敏感性增加。
Oncogene ( IF 6.9 ) Pub Date : 2020-02-17 , DOI: 10.1038/s41388-020-1208-5
Nina Struve ₁ , Zev A Binder ₂ , Lucy F Stead ₃ , Tim Brend ₃ , Stephen J Bagley ₄ , Claire Faulkner ₅ , Leonie Ott ₁ , Justus Müller-Goebel ₁ , Anna-Sophie Weik ₁ , Konstantin Hoffer ₁ , Leonie Krug _{1,

6} , Thorsten Rieckmann _{1,

6} , Lara Bußmann _{1,

6} , Marvin Henze _{1,

7} , Jennifer J D Morrissette ₈ , Kathreena M Kurian ₉ , Ulrich Schüller _{10,

11,

12} , Cordula Petersen _{1,

7} , Kai Rothkamm ₁ , Donald M O Rourke ₂ , Susan C Short ₃ , Malte Kriegs ₁

Affiliation

Laboratory of Radiobiology & Experimental Radiation Oncology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Leeds Institute of Medical Research at St James's, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, UK.
Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK.
Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Division of Precision and Computational Diagnostics, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Bristol Brain Tumour Research Centre, University of Bristol, Bristol, UK.
Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

癌基因表皮生长因子受体变异体 III (EGFRvIII) 经常在胶质母细胞瘤 (GBM) 中表达，但其对治疗反应的影响仍存在争议。在这里，我们想要测试 EGFRvIII 是否影响对烷化剂替莫唑胺 (TMZ) 的敏感性。因此，我们回顾性分析了 336 名 GBM 患者的生存情况，证明在包括 TMZ 在内的标准治疗下，EGFRvIII 表达与延长生存相关，但仅限于 O6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 启动子甲基化肿瘤的患者。使用具有内源性 EGFRvIII 表达的同基因 GBM 细胞系，我们可以证明 EGFRvIII 增加 TMZ 敏感性，并导致 TMZ 治疗后 DNA 双链断裂数量增加和明显的 S/G2 期停滞。我们观察到 EGFRvIII+ 细胞和患者肿瘤样本中 DNA 错配修复 (MMR) 蛋白的表达较高，其中 MSH2 和 MSH6 的表达最为明显。 EGFRvIII 特异性敲除降低了 MMR 蛋白表达，从而增加了 TMZ 耐药性。随后的功能激酶组分析显示，EGFRvIII 表达细胞中 p38 和 ERK1/2 依赖性信号传导的激活增加，从而调节 EGFRvIII 下游的 MMR 蛋白表达。总之，我们的结果表明，癌蛋白 EGFRvIII 通过 DNA MMR 的上调使部分 GBM 对当前标准护理治疗敏感。

"点击查看英文标题和摘要"

EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma.

The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR.

更新日期：2020-02-18

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