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

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.