S6K2 Inhibition Shows Potential in Overcoming MAPK Inhibitor–Resistant NRAS-Mutated Melanoma

By: Julia Cipriano, MS
Posted: Tuesday, February 25, 2025

The results of a preclinical study, which were published in the journal Science Translational Medicine, identified ribosomal protein S6 kinase 2 (S6K2) and its effector subnetwork as potential therapeutic targets for MAPK inhibitor–resistant NRAS-mutant melanoma. According to Jessie Villanueva, PhD, of Wistar Institute, Philadelphia, and colleagues, S6K2 inhibition induced cell death by disrupting lipid metabolism.

“Our findings underscore that MAPK inhibitor–resistant and –sensitive cells have different signaling dependencies both upstream and downstream of mTORC1 and illustrate specialized functions of S6K isoforms, highlighting the biologic importance of isoform differentiation,” the investigators commented. “Moreover, the identified [S6K2/PPARα] subnetwork provides a strategy to pharmacologically induce lethal lipid peroxidation in vivo, which has been limited by the lack of compounds with sufficient bioavailability.”

The investigators performed several laboratory analyses, including conventional immunoblotting, flow cytometry, RNA sequencing, reverse-phase protein array, global proteomics, and lipidomics, in melanoma cells. They found that silencing S6K2, but not S6K1, perturbed lipid metabolism, enhanced fatty acid unsaturation, and triggered lethal lipid peroxidation in MAPK inhibitor–resistant NRAS-mutated melanoma cells. Depletion of S6K2 appeared to induce endoplasmic reticulum stress and peroxisome proliferator–activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor–resistant melanoma. According to the investigators, in both patient-derived xenografts and immunocompetent murine melanoma models, combining PPARα agonists (eg, fenofibrate) with polyunsaturated fatty acids (eg, docosahexaenoic acid) phenocopied the effects of S6K2 abrogation and thus blocked tumor growth.

“Our findings suggest a clear path forward for more preclinical research on these treatment options,” concluded Brittany Lipchick, PhD, also of Wistar Institute, in an institutional press release. “Not only did our treatments work in the lab—they also appear to be quite safe. Some of the drugs we tested, like fenofibrate, are already safely used in humans for other purposes, so the road ahead is well-lit.”

Disclosure: For full disclosures of the study authors, visit science.org.

Science Translational Medicine