Abstract：
RAS proteins regulate cell division, differentiation and apoptosis via multiple downstream effector pathways. Oncogenic RAS variants are the commonest drivers in cancers, however they also drive many benign lesions predisposing to malignancy, such as melanocytic naevi, thyroid nodules, and colonic polyps. Reversal of these benign lesions could reduce cancer incidence, however the effects of oncogenic RAS have been notoriously difficult to target with downstream pathway inhibitors. Here we show effective suppression of oncogenic and currently undruggable NRASQ61K in primary cells from melanocytic naevi using siRNA targeted to the recurrent causal variant. This results in striking reduction in expression of ARL6IP1, a known inhibitor of endoplasmic reticulum stress-induced apoptosis not previously linked to NRAS. We go on to show that a single dose of siRNA in primary cells triggers an apoptotic cascade, in contrast to treatment with a MEK inhibitor. Protective packaging of the targeted siRNA into lipid nanoparticles permits successful delivery into a humanised mouse model of melanocytic naevi, and results in variant NRAS knockdown in vivo. These data show that RAS-induced protection from apoptosis is involved in persistence of NRAS-driven melanocytic naevi and anticipate that targeted siRNA could form the basis of clinical trials for RAS-driven benign tumours.
摘要：
RAS蛋白调节细胞分裂，通过多个下游效应子途径分化和凋亡。致癌RAS变异是癌症中最常见的驱动因素，然而，它们也驱动许多易患恶性肿瘤的良性病变，比如黑素细胞痣，甲状腺结节,结肠息肉.这些良性病变的逆转可以降低癌症发病率，然而,众所周知,下游途径抑制剂很难靶向致癌RAS的作用.在这里，我们显示了使用靶向复发性因果变异的siRNA在黑素细胞痣的原代细胞中有效抑制致癌和目前不可药物的NRASQ61K。这导致ARL6IP1的表达显着降低，ARL6IP1是一种已知的内质网应激诱导的凋亡抑制剂，以前与NRAS无关。我们继续证明，在原代细胞中单个剂量的siRNA会触发凋亡级联反应，与用MEK抑制剂治疗相反。将靶向siRNA保护性包装到脂质纳米颗粒中允许成功递送到黑素细胞痣的人源化小鼠模型中。并导致体内变异的NRAS敲低。这些数据表明，RAS诱导的细胞凋亡保护与NRAS驱动的黑素细胞痣的持久性有关，并预期靶向siRNA可以构成RAS驱动的良性肿瘤的临床试验基础。
