Abstract

RAS proteins regulate cell division, differentiation, and apoptosis through 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 nevi, 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. In this study, we show effective suppression of oncogenic and currently undruggable NRASQ61K in primary cells from melanocytic nevi using small interfering RNA 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 small interfering RNA in primary cells triggers an apoptotic cascade, in contrast to treatment with a MAPK/extracellular signal-regulated kinase kinase inhibitor. Protective packaging of the targeted small interfering RNA into lipid nanoparticles permits successful delivery into a humanized mouse model of melanocytic nevi 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 nevi and anticipate that targeted small interfering RNA could form the basis of clinical trials for RAS-driven benign tumors.