Abstract：
G protein-coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor-xenografted mouse models and patient-derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.
摘要：
G蛋白偶联受体(GPCRs)是最常见和最重要的药物靶标。然而,>70%的GPCR是不可用的或难以使用常规化学激动剂/拮抗剂靶向的。小核酸分子,可以序列特异性调节任何基因，提供了一个独特的机会，有效地扩大药物的目标，尤其是那些难以处理或难以处理的问题，比如GPCRs。这里,作者首次报道了小激活RNA（saRNA）有效调节GPCR用于癌症治疗。具体来说,saRNA促进MAS受体（MAS1）的表达，在癌细胞增殖和迁移中抵消经典血管紧张素II途径的GPCR，被识别。这些saRNA,由两亲性树枝状聚合物载体传递，增强MAS1表达，抵消血管紧张素II/血管紧张素II受体1型轴，并导致在肿瘤异种移植小鼠模型和患者来源的肿瘤模型中，肿瘤发生的显着抑制和多种癌症的肿瘤进展的抑制。这项研究不仅为靶向肾素-血管紧张素系统的癌症治疗提供了新的策略，也是通过RNA激活调节GPCR信号的新途径。
