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Updated: Aug 6, 2025

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ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma.

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  • 1Department of Dermatology, University of Zurich, University Hospital Zurich, Zurich, Switzerland.

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Targeting NRAS-mutated melanoma is difficult. Combining MEK inhibitors with ROS inducers overcomes resistance by targeting metabolic adaptations, improving treatment for melanoma and other cancers.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • NRAS-mutated melanomas are challenging to treat, with resistance to MAPK pathway inhibitors arising from complex adaptations.
  • Understanding these resistance mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To identify targetable vulnerabilities in NRAS-mutated melanoma resistant to MEK inhibition.
  • To explore novel combination therapies to overcome treatment resistance.

Main Methods:

  • Multiomics analyses (including single-cell RNA sequencing) were employed to characterize NRAS-mutated melanoma.
  • In vivo xenograft experiments and ex vivo pharmacoscopy of human metastatic melanomas were conducted.
  • Analysis of 486 cancer cell lines investigated oxidative stress response and translational suppression.

Main Results:

  • NRAS-mutated melanoma cells exhibit a mesenchymal phenotype and quiescent metabolism, conferring resistance to MEK inhibitors.
  • These resistant cells show heightened sensitivity to reactive oxygen species (ROS) induction due to metabolic alterations.
  • Combination therapy with a ROS inducer and MEK inhibitor effectively suppressed tumor growth and metastasis in preclinical models and human samples.
  • ROS-inducer sensitivity correlated with oxidative stress response and translational suppression across various cancer types.

Conclusions:

  • Metabolic reprogramming in drug-resistant NRAS-mutated melanoma creates a vulnerability to ROS induction.
  • Combining MEK inhibitors with ROS inducers represents a promising therapeutic strategy for NRAS-mutated melanoma and potentially other cancers.
  • Targeting metabolic adaptations and oxidative stress offers a new avenue for overcoming therapeutic resistance.