Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor–resistant <i>NRAS</i> -mutant melanoma
Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in <i>NRAS</i>-mutant (<i>NRAS</i><sup>MUT</sup>) 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 <i>NRAS</i><sup>MUT</sup> 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 <i>NRAS</i><sup>MUT</sup> melanomas that are resistant to global MAPK pathway inhibitors.
Authors
- Gordon Brent Mills (ORCID: https://orcid.org/0000-0002-0144-9614)
- Patricia Reyes-Uribe
- Andrew V. Kossenkov (ORCID: https://orcid.org/0000-0002-1536-0418)
- Brittany C. Lipchick (ORCID: https://orcid.org/0000-0002-7326-0079)
- Yiling Lu (ORCID: https://orcid.org/0000-0002-3662-2106)
- David W. Speicher (ORCID: https://orcid.org/0000-0003-1311-4261)
- Adam N. Guterres (ORCID: https://orcid.org/0000-0002-4607-2099)
- Aaron R. Goldman (ORCID: https://orcid.org/0000-0001-7605-9592)
- Subhasree Basu (ORCID: https://orcid.org/0009-0008-0969-800X)
- Maureen E. Murphy (ORCID: https://orcid.org/0000-0001-7644-7296)
- Jessie Villanueva (ORCID: https://orcid.org/0000-0001-5701-2609)
- Delaine M. Zundell
- Qin Liu (ORCID: https://orcid.org/0000-0001-9964-580X)
- Hsin-Yi Chen (ORCID: https://orcid.org/0000-0003-2950-255X)
- Xiangfan Yin
- Segundo W Del Aguila (ORCID: https://orcid.org/0000-0003-3221-8234)
- Yulissa Tirado
Institutions
- The Wistar Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Oregon Health & Science University (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1126/scitranslmed.adp8913
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Pennsylvania Department of Health
- Melanoma Research Alliance
- Ohio State University
- National Institutes of Health
- National Cancer Institute