强调基于适配体的策略治疗egfrviii阳性胶质母细胞瘤的潜力

S. Camorani, L. Cerchia
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引用次数: 1

摘要

表皮生长因子受体变异III (EGFRvIII)是胶质母细胞瘤(GBM)中最常见的EGFR突变体。由于大部分细胞外区域被截断,EGFRvIII不能结合任何配体,也不能向下游效应分子发出组成性信号。它具有肿瘤特异性,高致癌性,通常与EGFR野生型(EGFRwt)共表达。EGFR酪氨酸激酶抑制剂(TKIs)已被证明在GBM中无效,不同的机制解释了对此类抑制剂的耐药发生。其中,EGFR TKIs诱导转向血小板衍生生长因子受体β (PDGFRβ)的表达和信号传导,从而使肿瘤依赖于这种受体持续生长和抵抗治疗。在我们最近的研究中,我们发现了一种名为CL4的核酸酶抗性RNA适配体能够结合并抑制EGFRvIII,从而阻碍EGFRvIII阳性GBM细胞的增殖、迁移和侵袭。重要的是,CL4和EGFR TKIs都与先前验证的抗pdgfr β适配体合作,抑制细胞生长。在这里,我们强调了EGFRvIII适配体阻碍EGFRvIII与其他受体酪氨酸激酶(rtk)和负责GBM发生和进展的细胞表面蛋白的功能相互作用的潜力。CL4作为靶向配体的药物递送方法的效用也进行了讨论。总之,基于适配体的分子在不久的将来对GBM的管理具有重要意义。
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Highlighting the potential of aptamer-based strategy to treat EGFRvIII-positive glioblastoma
Epidermal growth factor receptor variant III (EGFRvIII) is the most common EGFR mutant found in glioblastoma (GBM). Due to a truncation of large portion of the extracellular region, EGFRvIII  is unable to bind any ligand and constitutively signals to downstream effector molecules. It is tumor-specific, highly oncogenic and usually co-expressed with EGFR wild type (EGFRwt). EGFR tyrosine kinase inhibitors (TKIs) have proven ineffective in GBM and different mechanisms account for the occurrence of resistance to such inhibitors. Among these, EGFR TKIs induce a  switch to platelet-derived growth factor receptor β (PDGFRβ) expression and signaling, thus rendering the tumors addicted to such receptor for continued growth and resistance to treatment. In our recent investigation, we showed the ability of a nuclease-resistant RNA aptamer, named CL4, to bind and inhibit EGFRvIII thus hampering proliferation, migration and invasion of EGFRvIII-positive GBM cells. Importantly, both CL4 and EGFR TKIs cooperate with a previously validated anti-PDGFRβ aptamer in inhibiting cell growth. Here, we highlight the potential of the EGFRvIII aptamer to hamper the EGFRvIII functional interplay with other receptor tyrosine kinases (RTKs) and cell surface proteins responsible for GBM development and progression. The utility of CL4 as targeting ligand for drug-delivery approaches is also discussed. Overall, aptamer-based molecules have significant implications for managing GBM in the near future.
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