RNA Therapy for Oncogenic NRAS-Driven Nevi Induces Apoptosis.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Oncogenic RAS variants are key drivers of various cancers and benign lesions like melanocytic nevi.
• Targeting oncogenic RAS directly has been challenging due to difficulties with downstream pathway inhibitors.

Purpose of the Study:

• To investigate the efficacy of small interfering RNA (siRNA) targeting the NRAS^Q61K variant in primary melanocytic nevus cells.
• To explore the downstream effects of NRAS^Q61K suppression, including its impact on apoptosis and endoplasmic reticulum stress.

Main Methods:

• Utilized siRNA targeted to the NRAS^Q61K variant in primary melanocytic nevus cells.
• Investigated the expression of ARL6IP1 and its role in apoptosis.
• Administered siRNA encapsulated in lipid nanoparticles to a humanized mouse model of melanocytic nevi.

Main Results:

• Effective suppression of oncogenic NRAS^Q61K was achieved in primary cells.
• siRNA treatment led to a significant reduction in ARL6IP1 expression and triggered an apoptotic cascade.
• In vivo delivery of siRNA in a mouse model resulted in NRAS knockdown and demonstrated a reduction in melanocytic nevi.

Conclusions:

• RAS-mediated protection from apoptosis contributes to the persistence of NRAS-driven melanocytic nevi.
• Targeted siRNA represents a promising therapeutic strategy for RAS-driven benign tumors, potentially reducing cancer incidence.