The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma.

The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma.

Publication date: Feb 22, 2024

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 (AC004540. 4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS 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 T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

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Concepts Keywords
Ac004540 Antisense oligonucleotides
Death Apoptosis
Nuclear hnRNPA2/B1
Tumorigenesis HT-KAM
Unbiased lncRNA
MAPK-pathway
Melanoma
T-RECS

Semantics

Type Source Name
disease MESH cancer
disease MESH melanoma
pathway KEGG Melanoma
disease MESH tumorigenesis
pathway REACTOME Reproduction
drug DRUGBANK Coenzyme M
disease MESH Allergy
disease MESH death
pathway KEGG Apoptosis
pathway KEGG MAPK signaling pathway
disease MESH noma
disease MESH alcoholic fatty liver
disease MESH carcinoma
drug DRUGBANK Ranitidine
drug DRUGBANK Trestolone
drug DRUGBANK Topiramate
drug DRUGBANK L-Valine
drug DRUGBANK Esomeprazole
drug DRUGBANK Honey
disease MESH metastasis
drug DRUGBANK Huperzine B
drug DRUGBANK Formaldehyde
drug DRUGBANK Gentian violet cation
drug DRUGBANK Phenol
drug DRUGBANK Isoamyl alcohol
drug DRUGBANK Indoleacetic acid
drug DRUGBANK ATP
drug DRUGBANK Tromethamine
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Ademetionine
drug DRUGBANK Cysteamine
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Water
drug DRUGBANK Pralatrexate
drug DRUGBANK Dextrose unspecified form
drug DRUGBANK Ethanol
drug DRUGBANK Medical air
drug DRUGBANK Aspartame
drug DRUGBANK Hyaluronic acid

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