Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRASmut melanoma
Chen, H.-Y.; Goldman, A. R.; Zayas-Bazan, D.; Reyes-Uribe, P. I.; Guterres, A. N.; Lipchick, B.; Basu, S.; Yin, X.; Axelrod, M. J.; Lu, Y.; Schug, Z.; Kossenkov, A. V.; Mills, G. B.; Liu, Q.; Weber, M. J.; Murphy, M. E.; Speicher, D. W.; Villanueva, J.
Show abstract
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 PPAR activation, triggering cell death selectively in MAPKi-resistant melanoma. We show that combining PPAR 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 SummaryS6K2 is a vulnerability in MAPK inhibitor-resistant NRAS-mutant melanoma
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