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Background <p>Melanoma is an aggressive form of skin cancer, and patients with <i>NRAS</i>-mutant melanoma face limited treatment options due to the lack of direct NRAS inhibitors. This study explores the utilization of antisense oligonucleotides (ASOs) to directly target <i>NRAS</i>-mRNA for therapeutic approaches.</p> Methods <p>We designed and tested <i>NRAS</i>-mRNA-targeting ASOs. Experiments in melanoma cell lines and mouse models assessed effects on cell survival, apoptosis, and tumor growth. A kinase activity profiling platform identified therapeutically exploitable pathways influenced by NRAS suppression.</p> Results <p>Our research suggests that ASOs do not need to target the mutated NRAS segment to be effective. ASOs designed for the non-mutated NRAS sequence eliminate NRAS-dependent melanoma cells while sparing NRAS wild-type cells. They act independently of subcellular target localization, reduce NRAS-mRNA levels, inhibit MAPK signaling, induce apoptosis, and suppress melanoma growth in vitro and in vivo. Outcomes of high-throughput kinase activity mapping (HT-KAM) indicate a significant dependency between <i>NRAS</i>-mRNA expression and the activity of MEK1, FGFR2, and CDK4 kinases. Co-targeting these kinases enhances the antiproliferative effect of NRAS ASOs, showing synergy.</p> Conclusions <p>These findings highlight antisense oligonucleotides as a promising therapeutic approach for <i>NRAS</i>-mutant melanoma. By effectively blocking <i>NRAS</i>-mRNA, this strategy overcomes challenges posed by the absence of a direct small molecule inhibitor for NRAS, and may offer new treatment options for patients.</p>

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Suppression of NRAS-mutant melanoma growth with NRAS-targeting Antisense Oligonucleotide treatment reveals therapeutically relevant kinase co-dependencies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月5日

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  • Valentin Feichtenschlager,
  • Yixuan James Zheng,
  • Tiange Qu,
  • Dasha Hohlova,
  • Ciara Callanan,
  • Linan Chen,
  • Christopher Chen,
  • Wilson Ho,
  • Albert Lee,
  • Yeonjoo Hwang,
  • Arowyn Courtright,
  • Thy Nguyen,
  • Olivia Marsicovetere,
  • Denise P. Muñoz,
  • Klemens Rappersberger,
  • Jean-Philippe Coppe,
  • Susana Ortiz-Urda

摘要

Background

Melanoma is an aggressive form of skin cancer, and patients with NRAS-mutant melanoma face limited treatment options due to the lack of direct NRAS inhibitors. This study explores the utilization of antisense oligonucleotides (ASOs) to directly target NRAS-mRNA for therapeutic approaches.

Methods

We designed and tested NRAS-mRNA-targeting ASOs. Experiments in melanoma cell lines and mouse models assessed effects on cell survival, apoptosis, and tumor growth. A kinase activity profiling platform identified therapeutically exploitable pathways influenced by NRAS suppression.

Results

Our research suggests that ASOs do not need to target the mutated NRAS segment to be effective. ASOs designed for the non-mutated NRAS sequence eliminate NRAS-dependent melanoma cells while sparing NRAS wild-type cells. They act independently of subcellular target localization, reduce NRAS-mRNA levels, inhibit MAPK signaling, induce apoptosis, and suppress melanoma growth in vitro and in vivo. Outcomes of high-throughput kinase activity mapping (HT-KAM) indicate a significant dependency between NRAS-mRNA expression and the activity of MEK1, FGFR2, and CDK4 kinases. Co-targeting these kinases enhances the antiproliferative effect of NRAS ASOs, showing synergy.

Conclusions

These findings highlight antisense oligonucleotides as a promising therapeutic approach for NRAS-mutant melanoma. By effectively blocking NRAS-mRNA, this strategy overcomes challenges posed by the absence of a direct small molecule inhibitor for NRAS, and may offer new treatment options for patients.