表皮生长因子受体扩增和 EGFRvIII 预测并参与了 TAT-Cx43266-283 在临床前胶质母细胞瘤模型中的抗肿瘤反应。

EGFR amplification and EGFRvIII predict and participate in TAT-Cx43266-283 antitumor response in preclinical glioblastoma models.

机构信息

Department of Biochemistry and Molecular Biology, Neuroscience Institute of Castilla y León (INCyL), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.

Centre for Cancer Research-IBMCC (CSIC), IBSAL, Salamanca, Spain.

出版信息

Neuro Oncol. 2024 Jul 5;26(7):1230-1246. doi: 10.1093/neuonc/noae060.

DOI:10.1093/neuonc/noae060

PMID:38507464

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11226870/

Abstract

BACKGROUND

Glioblastoma (GBM) commonly displays epidermal growth factor receptor (EGFR) alterations (mainly amplification and EGFRvIII) and TAT-Cx43266-283 is a Src-inhibitory peptide with antitumor properties in preclinical GBM models. Given the link between EGFR and Src, the aim of this study was to explore the role of EGFR in the antitumor effects of TAT-Cx43266-283.

METHODS

The effect of TAT-Cx43266-283, temozolomide (TMZ), and erlotinib (EGFR inhibitor) was studied in patient-derived GBM stem cells (GSCs) and murine neural stem cells (NSCs) with and without EGFR alterations, in vitro and in vivo. EGFR alterations were analyzed by western blot and fluorescence in situ hybridization in these cells, and compared with Src activity and survival in GBM samples from The Cancer Genome Atlas.

RESULTS

The effect of TAT-Cx43266-283 correlated with EGFR alterations in a set of patient-derived GSCs and was stronger than that exerted by TMZ and erlotinib. In fact, TAT-Cx43266-283 only affected NSCs with EGFR alterations, but not healthy NSCs. EGFR alterations correlated with Src activity and poor survival in GBM patients. Finally, tumors generated from NSCs with EGFR alterations showed a decrease in growth, invasiveness, and vascularization after treatment with TAT-Cx43266-283, which enhanced the survival of immunocompetent mice.

CONCLUSIONS

Clinically relevant EGFR alterations are predictors of TAT-Cx43266-283 response and part of its mechanism of action, even in TMZ- and erlotinib-resistant GSCs. TAT-Cx43266-283 targets NSCs with GBM-driver mutations, including EGFR alterations, in an immunocompetent GBM model in vivo, suggesting a promising effect on GBM recurrence. Together, this study represents an important step toward the clinical application of TAT-Cx43266-283.

摘要

背景

胶质母细胞瘤（GBM）通常表现出表皮生长因子受体（EGFR）改变（主要是扩增和 EGFRvIII），TAT-Cx43266-283 是一种具有抗肿瘤特性的Src 抑制肽，在临床前 GBM 模型中。鉴于 EGFR 和 Src 之间的联系，本研究旨在探讨 EGFR 在 TAT-Cx43266-283 抗肿瘤作用中的作用。

方法

在体外和体内研究了 TAT-Cx43266-283、替莫唑胺（TMZ）和厄洛替尼（EGFR 抑制剂）在有和没有 EGFR 改变的患者来源的 GBM 干细胞（GSCs）和鼠神经干细胞（NSCs）中的作用。通过 Western blot 和荧光原位杂交分析这些细胞中的 EGFR 改变，并与癌症基因组图谱中 GBM 样本中的 Src 活性和存活率进行比较。

结果

TAT-Cx43266-283 的作用与一组患者来源的 GSCs 中的 EGFR 改变相关，其作用强于 TMZ 和厄洛替尼。事实上，TAT-Cx43266-283 仅影响具有 EGFR 改变的 NSCs，但不影响健康的 NSCs。EGFR 改变与 GBM 患者的 Src 活性和不良预后相关。最后，用 TAT-Cx43266-283 治疗后，具有 EGFR 改变的 NSCs 生成的肿瘤生长、侵袭和血管生成减少，从而提高了免疫功能正常的小鼠的存活率。

结论

临床相关的 EGFR 改变是 TAT-Cx43266-283 反应的预测因子，也是其作用机制的一部分，即使在 TMZ 和厄洛替尼耐药的 GSCs 中也是如此。TAT-Cx43266-283 靶向具有 GBM 驱动突变的 NSCs，包括 EGFR 改变，在体内免疫功能正常的 GBM 模型中，这表明它对 GBM 复发有潜在的影响。总之，这项研究是 TAT-Cx43266-283 临床应用的重要一步。