Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor–resistant NRAS-mutant melanoma

Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant (NRAS^MUT) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in NRAS^MUT melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator–activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor–resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRAS^MUT melanomas that are resistant to global MAPK pathway inhibitors.