Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRASMUT melanoma

Although oncogenic NRAS activates MAPK signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant tumors. Here we report that 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 selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces ER stress, and PPARα activation, triggering cell death selectively in MAPKi-resistant melanoma. We show that combining PPARα agonists and polyunsaturated fatty acids phenocopies the effects of S6K2 abrogation, blocking tumor growth in PDX and immunocompetent mouse pre-clinical models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRAS-mutant melanoma that are resistant to global MAPK pathway inhibitors. One Sentence Summary S6K2 is a vulnerability in MAPK inhibitor-resistant NRAS-mutant melanoma ### Competing Interest Statement Gordon B. Mills serves as a consultant for AstraZeneca, Chrysallis Biotechnology, Immunomet, Ionis, Nuevolution, PDX Pharma, SignalChem Lifesciences, Symptomen, Tarveda; owns stock in Catena Pharma, ImmunoMet, SignalChem, Spindle Top Ventures, Tarveda; and has received research funding from AstraZeneca, Nanostring, Pfizer, Takeda/Millennium, and Tesaro. All the other authors declare no COI.