Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22904-4741, USA; Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Chemical Engineering, University of Virginia, Charlottesville, VA 22904-4741, USA.
Mol Ther. 2021 Apr 7;29(4):1585-1601. doi: 10.1016/j.ymthe.2020.12.019. Epub 2020 Dec 15.
Suicide gene therapies provide a unique ability to target cancer cells selectively, often based on modification of viral tropism or transcriptional regulation of therapeutic gene expression. We designed a novel suicide gene therapy approach wherein the gene product (herpes simplex virus thymidine kinase or yeast cytosine deaminase) is phosphorylated and stabilized in expression by the extracellular signal-regulated kinase (ERK), which is overactive in numerous cancers with elevated expression or mutation of receptor tyrosine kinases or the GTPase RAS. In contrast to transcriptional strategies for selectivity, regulation of protein stability by ERK allows for high copy expression via constitutive viral promoters, while maintaining tumor selectivity in contexts of elevated ERK activity. Thus, our approach turns a signaling pathway often coopted by cancer cells for survival into a lethal disadvantage in the presence of a chimeric protein and prodrug, as highlighted by a series of in vitro and in vivo examples explored here.
自杀基因治疗为选择性靶向癌细胞提供了独特的能力，通常基于病毒趋向性的修饰或治疗基因表达的转录调控。我们设计了一种新的自杀基因治疗方法，其中基因产物（单纯疱疹病毒胸苷激酶或酵母胞嘧啶脱氨酶）通过细胞外信号调节激酶（ERK）磷酸化和稳定表达，而 ERK 在许多癌症中过度活跃，这些癌症中受体酪氨酸激酶或 GTP 酶 RAS 的表达或突变升高。与选择性的转录策略相反，ERK 对蛋白质稳定性的调节允许通过组成性病毒启动子进行高拷贝表达，同时在 ERK 活性升高的情况下保持肿瘤选择性。因此，我们的方法将癌细胞经常为了生存而采用的信号通路转化为嵌合蛋白和前药存在时的致命劣势，正如这里探讨的一系列体外和体内实例所强调的那样。
