EGF受体活性向无EGF区的扩散与肿瘤的分子治疗
Spreading of EGF Receptor Activity into EGF-free Regions and Molecular Therapies of Cancer
摘要：
表皮生长因子受体（EGFR）的主要活化已经成为针对几种形式的癌症的分子疗法的突出靶标。但是，尽管在过去几年中取得了相当大的进展，但对它的许多方面仍然知之甚少。关于受体活性横向扩散到无配体区域的实验挑战了EGFR激活的当前标准模型。在这里，我们提出并研究了一个理论模型，该模型解释了扩散到无配体区域而不引入任何新的未知动力学参数。该模型表现出双稳态的活性，诱导的通用反应机制，其中包括通过二聚活化和通过米氏反应失活。它具有慢传播的前沿解决方案和更快的初始瞬态。我们分析了有关的实验，发现它们与快速传播的初始模式是定量一致的，而与慢传播的波前不一致。我们指出，活性的横向扩散与在癌细胞中观察到的持续受体活性的病理水平有关，并将这种联系用于设计和快速评价靶向EGFR主要活化的分子疗法。
英文摘要：
The primary activation of the epidermal growth factor receptor (EGFR) has become a prominent target for molecular therapies against several forms of cancer. But despite considerable progress during the last years, many of its aspects remain poorly understood. Experiments on lateral spreading of receptor activity into ligand-free regions challenge the current standard models of EGFR activation. Here, we propose and study a theoretical model, which explains spreading into ligand-free regions without introducing any new, unknown kinetic parameters. The model exhibits bistability of activity, induced by a generic reaction mechanism, which consists of activation via dimerization and deactivation via a Michaelis-Menten reaction. It possesses slow propagating front solutions and faster initial transients. We analyze relevant experiments and find that they are in quantitative accordance with the fast initial modes of spreading, but not with the slow propagating front. We point out that lateral spreading of activity is linked to pathological levels of persistent receptor activity as observed in cancer cells and exemplify uses of this link for the design and quick evaluation of molecular therapies targeting primary activation of EGFR.
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