Departments of Molecular Medicine, Markusovszky Hospital, Markusovszky Street 5, 9700 Szombathely, Hungary.
Neuromolecular Med. 2013 Jun;15(2):420-34. doi: 10.1007/s12017-013-8229-y. Epub 2013 Apr 11.
Glioblastoma represents one of the most challenging problems in neurooncology. Among key elements driving its behavior is the transmembrane epidermal growth factor receptor family, with the first member epidermal growth factor receptor (EGFR) centered in most studies. Engagement of the extracellular domain with a ligand activates the intracellular tyrosine kinase (TK) domain of EGFR, leading to autophosphorylation and signal transduction that controls proliferation, gene transcription, and apoptosis. Oncogenic missense mutations, deletions, and insertions in the EGFR gene are preferentially located in the extracellular domain in glioblastoma and cause constitutive activation of the receptor. The mutant EGFR may also transactivate other cell surface molecules, such as additional members of the EGFR family and the platelet-derived growth factor receptor, which ignite signaling cascades that synergize with the EGFR-initiated cascade. Because of the cell surface location and increased expression of the receptor along with its important biological function, EGFR has triggered much effort for designing targeted therapy. These approaches include TK inhibition, monoclonal antibody, vaccine, and RNA-based downregulation of the receptor. Treatment success requires that the drug penetrates the blood-brain barrier and has low systemic toxicity but high selectivity for the tumor. While the blockade of EGFR-dependent processes resulted in experimental and clinical treatment success, cells capable of using alternative signaling ultimately escape this strategy. A combination of interventions targeting tumor-specific cell surface regulators along with convergent downstream signaling pathways will likely enhance efficacy. Studies on EGFR in glioblastoma have revealed much information about the complexity of gliomagenesis and also facilitated the development of strategies for targeting drivers of tumor growth and combination therapies with increasing complexity.
胶质母细胞瘤是神经肿瘤学中最具挑战性的问题之一。在驱动其行为的关键因素中，跨膜表皮生长因子受体家族首当其冲，其中第一个成员表皮生长因子受体（EGFR）是大多数研究的中心。配体与细胞外结构域的结合激活 EGFR 的细胞内酪氨酸激酶（TK）结构域，导致控制增殖、基因转录和细胞凋亡的自身磷酸化和信号转导。EGFR 基因的致癌错义突变、缺失和插入优先位于胶质母细胞瘤的细胞外结构域，导致受体的组成性激活。突变的 EGFR 也可能转激活其他细胞表面分子，如 EGFR 家族的其他成员和血小板衍生生长因子受体，从而引发与 EGFR 起始级联协同作用的信号级联。由于受体的细胞表面位置和表达增加及其重要的生物学功能，EGFR 引发了设计靶向治疗的大量努力。这些方法包括 TK 抑制、单克隆抗体、疫苗和基于 RNA 的受体下调。治疗成功需要药物穿透血脑屏障，具有低系统毒性但对肿瘤具有高选择性。虽然阻断 EGFR 依赖性过程在实验和临床治疗中取得了成功，但能够利用替代信号的细胞最终会逃避这种策略。针对肿瘤特异性细胞表面调节剂以及收敛性下游信号通路的联合干预措施可能会提高疗效。关于 EGFR 在胶质母细胞瘤中的研究揭示了许多关于胶质瘤发生的复杂性的信息，并且还促进了针对肿瘤生长驱动因素的靶向策略和组合疗法的发展，这些策略的复杂性不断增加。
