EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications
EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications
复制标题
DOI：
10.1038/onc.2014.448
复制
发表时间：
2015-10-08
期刊：
影响因子：
8
通讯作者：
Johns, T. G.
中科院分区：
文献类型：
--
作者：
Greenall, S. A.;Donoghue, J. F.;Johns, T. G.
表皮生长因子受体的截短突变体 EGFRvIII 通常在神经胶质瘤（一种无法治愈的脑癌）中表达。 EGFRvIII 具有致瘤性，部分原因在于其反式激活其他受体酪氨酸激酶 (RTK)。防止这种反式激活的影响可能成为神经胶质瘤有效治疗的一部分。然而，反式激活发生的机制尚不清楚。重点关注 RTK MET，我们发现 U87MG 人胶质瘤细胞体外的 MET 反式激活与 EGFRvIII 活性成正比，并且涉及与粘着斑激酶 (FAK) 支架相关的 MET 异二聚化。然而，某些其他 RTK 的反式激活独立于 FAK。在颅内神经胶质瘤小鼠模型中，同时靶向 EGFRvIII（使用帕尼单抗）和反式激活的 RTK 本身（使用莫特塞尼）可比单独使用任一药物获得显着更高的生存率，表明共同靶向这些 RTK 具有有效的抗肿瘤功效，并为治疗通常难以治疗的表达 EGFRvIII 的神经胶质瘤提供了一种策略。
A truncation mutant of the epidermal growth factor receptor, EGFRvIII, is commonly expressed in glioma, an incurable brain cancer. EGFRvIII is tumorigenic, in part, through its transactivation of other receptor tyrosine kinases (RTKs). Preventing the effects of this transactivation could form part of an effective therapy for glioma; however, the mechanism by which the transactivation occurs is unknown. Focusing on the RTK MET, we show that MET transactivation in U87MG human glioma cells in vitro is proportional to EGFRvIII activity and involves MET heterodimerization associated with a focal adhesion kinase (FAK) scaffold. The transactivation of certain other RTKs was, however, independent of FAK. Simultaneously targeting EGFRvIII (with panitumumab) and the transactivated RTKs themselves (with motesanib) in an intracranial mouse model of glioma resulted in significantly greater survival than with either agent alone, indicating that cotargeting these RTKs has potent antitumor efficacy and providing a strategy for treating EGFRvIII-expressing gliomas, which are usually refractory to treatment.