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.

doi:10.1101/2021.04.07.438684

bioRxiv · 10.1101/2021.04.07.438684

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.

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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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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.. 2021-04-07. Selective abrogation of S6K2 maps lipid homeostasis as a survival vulnerability in MAPKi-resistant NRASmut melanoma. https://doi.org/10.1101/2021.04.07.438684

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