The therapeutically actionable long non-coding RNA '' is essential to cancer cells' survival in NRAS/MAPK-driven melanoma.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA () that is upregulated in NRAS/MAPK-dependent melanoma, and that we named . Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impacton normal primary melanocytes. Mechanistically, treatment with ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.