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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

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The therapeutically actionable long non-coding RNA 'T-RECS' is essential to cancer cells' survival in

Valentin Feichtenschlager1,2, Linan Chen3, Yixuan James Zheng3,4

  • 1Department of Dermatology, Mt Zion Cancer Research Center, University of California San Francisco, 2340 Sutter Street, Room N461, San Francisco, CA, 94115, USA. valentin.feichtenschlager@hotmail.com.

Molecular Cancer
|February 21, 2024
PubMed

Insights

Targeting the T-RECS long non-coding RNA with antisense oligonucleotides (ASOs) effectively suppressed NRAS-mutated melanoma growth and induced cell death, offering a promising new therapeutic strategy for this challenging cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • RNA Therapeutics

Background:

  • NRAS-mutated melanoma presents significant therapeutic challenges.
  • Long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators in cancer development.
  • Identifying novel targets is crucial for advancing melanoma treatment.

Purpose of the Study:

  • To identify and characterize novel therapeutic targets in NRAS-mutated melanoma.
  • To evaluate the therapeutic potential of targeting the lncRNA T-RECS using antisense oligonucleotides (ASOs).

Main Methods:

  • Utilized a combination of experimental models, computational analysis, and patient biospecimens for lncRNA discovery.
  • Designed and tested T-RECS-specific antisense oligonucleotides (ASOs) in melanoma cell lines and xenograft models.
  • Investigated the molecular mechanisms underlying T-RECS ASO activity, including kinase signaling and protein stability.

Main Results:

  • Identified T-RECS (AC004540.4), a nuclear-enriched lncRNA upregulated in NRAS/MAPK-dependent melanoma.
  • T-RECS ASOs demonstrated potent antimelanoma activity, reducing cell growth and inducing apoptosis with minimal toxicity to normal cells.
  • ASO treatment downregulated pro-survival kinases and reduced hnRNPA2/B1 stability, impacting MAPK signaling.
  • Systemic ASO treatment significantly suppressed tumor growth in preclinical models without observable toxicity.

Conclusions:

  • T-RECS is a validated therapeutic target in NRAS-mutated melanoma.
  • ASO-mediated inhibition of T-RECS is a viable and promising RNA-targeting strategy for melanoma.
  • This approach offers a potential new avenue for treating MAPK pathway-activated melanoma.
Keywords:
Antisense oligonucleotidesApoptosisHT-KAMMAPK-pathwayMelanomaT-RECShnRNPA2/B1lncRNA

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