Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity.
Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity.
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DOI：
10.1186/1752-0509-5-156
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发表时间：
2011-10-04
影响因子：
--
通讯作者：
Merajver SD
中科院分区：
文献类型：
--
作者：
Wynn ML;Ventura AC;Sepulchre JA;García HJ;Merajver SD
在实验和理论工作中已经表明，共价修饰的信号级联通过称为追溯性的现象自然地表现出双向信号传播。由于共价修饰的信号级联中的酶螯合而产生的追溯性的一个重要后果是下游扰动可以在扰动上游的组分中产生响应，而不需要明确的反馈连接。因此，追溯性可能在细胞对靶向治疗的反应中发挥重要作用。激酶抑制剂是一类靶向治疗药物，旨在干扰失调信号通路中的特定激酶分子。尽管激酶抑制剂作为抗癌剂非常有前途，但其可能通过非特异性相互作用或通路串扰产生不期望的脱靶效应。我们假设，靶向治疗，如激酶抑制剂，可以产生脱靶效应作为一个后果的追溯性。我们使用了一个计算模型和一系列简单的信号基序来验证这一假设。我们的结果表明，在所有参数的生理和治疗相关范围内，靶向抑制剂可以通过追溯性自然诱导脱靶效应。在我们的模型中，控制信号网络中共价修饰循环的动力学对于传播上游脱靶效应比控制靶向治疗本身的动力学更重要。我们的研究结果还揭示了令人惊讶的和关键的结果，激酶抑制剂有能力打开“”，否则“关闭”平行级联时，两个级联共享上游激活剂。通路结构的适当和详细表征对于鉴定靶向的最佳蛋白质以及以安全和有效的方式调节通路所需的靶向治疗浓度是重要的。我们相信我们的研究结果支持这样的立场，即这种表征应该考虑追溯性作为激酶抑制剂和其他靶向治疗诱导的脱靶效应的一个强大的潜在来源。
It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone. We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator. A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective manner. We believe our results support the position that such characterizations should consider retroactivity as a robust potential source of off-target effects induced by kinase inhibitors and other targeted therapies.
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