Selective Abrogation of S6K2 Identifies Lipid Homeostasis as a Survival Vulnerability in MAPK Inhibitor–Resistant NRAS-Mutant Melanoma

Oncology Medicine Immunology Biochemistry Life Sciences Cell Biology
NRAS-mutant melanoma MAPK inhibitor resistance lipid metabolism S6K2 PPARα

Academic Background

NRAS-mutant (NRASmut) melanoma is a highly aggressive tumor type, accounting for nearly 30% of all melanoma cases. NRAS is an oncogene that persistently activates the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a critical role in melanoma development. However, despite extensive research on MAPK pathway inhibitors (MAPKi), their therapeutic efficacy in NRASmut melanoma remains limited, with single-agent response rates below 20% and no significant improvement in patient survival. Moreover, inhibition of the MAPK pathway often leads to feedback activation of the PI3K/AKT pathway. Although simultaneous inhibition of MAPK and PI3K pathways may enhance efficacy, this strategy has caused significant toxicity in patients, and clinically effective doses have yet to be identified. Therefore, identifying specific therapeutic targets for MAPKi-resistant (MAPKi-R) NRASmut melanoma has become a key focus of current research.

Source of the Paper

This research paper was authored by Brittany Lipchick et al., with team members from several prominent research institutions, including the Wistar Institute, the University of Texas MD Anderson Cancer Center, and the Knight Cancer Institute. The paper was published on February 5, 2025, in Science Translational Medicine, titled “Selective Abrogation of S6K2 Identifies Lipid Homeostasis as a Survival Vulnerability in MAPK Inhibitor–Resistant NRAS-Mutant Melanoma.”

Research Process and Results

1. Key Role of S6K2 in MAPKi-Resistant Melanoma

The study first analyzed the heterogeneous responses of NRASmut melanoma cells to MAPKi. By comparing MAPKi-sensitive (MAPKi-S) and MAPKi-R cells, the researchers found that although MAPKi effectively inhibits the MAPK pathway, the expression of S6K2 (40S ribosomal protein S6 kinase 2) was significantly elevated in resistant cells, while S6K1 expression showed heterogeneity. Further RNA sequencing (RNA-seq) and Western blot analyses confirmed that S6K2 expression is higher in MAPKi-R cells and is associated with poor patient prognosis.

2. S6K2 Depletion Induces Lipid Metabolism Disruption and Cell Death

To explore the role of S6K2 in MAPKi-R cells, the researchers specifically knocked down S6K2 expression using RNA interference (RNAi). The results showed that S6K2 depletion significantly induced cell death in MAPKi-R cells, whereas S6K1 knockdown did not produce a similar effect. Further studies revealed that S6K2 depletion disrupted cellular lipid metabolism, particularly leading to the accumulation of polyunsaturated fatty acids (PUFAs), which triggered lipid peroxidation and oxidative stress. Lipidomics analysis demonstrated that S6K2 depletion significantly increased the PUFA content in lipid classes such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol.

3. S6K2 Depletion Activates Endoplasmic Reticulum Stress and PPARα Signaling

Transcriptomic analysis showed that S6K2 depletion significantly activated the unfolded protein response (UPR), particularly the IRE1α-XBP1 signaling pathway, while upregulating the expression of peroxisome proliferator-activated receptor α (PPARα) and its target genes. Notably, treatment with the IRE1α inhibitor KIRA6 or the broad-spectrum caspase inhibitor ZVAD partially reversed the cell death induced by S6K2 depletion, indicating that S6K2 depletion triggers apoptosis by activating UPR and PPARα signaling.

4. Combination of PPARα Agonists and PUFAs Mimics S6K2 Depletion Effects

Based on the lipid metabolism disruption and oxidative stress induced by S6K2 depletion, the researchers further explored the therapeutic effects of combining PPARα agonists (e.g., fenofibrate, FNB) with PUFAs (e.g., docosahexaenoic acid, DHA). The study found that the combination of FNB and DHA significantly induced lipid peroxidation and cell death in MAPKi-R cells, but no similar effect was observed in MAPKi-S cells. Additionally, in vivo experiments demonstrated that the combination of FNB and DHA significantly suppressed tumor growth in NRASmut melanoma mouse models without apparent toxicity.

Conclusion

This study highlights the critical role of S6K2 in MAPKi-resistant NRASmut melanoma and proposes a novel therapeutic strategy targeting S6K2 or its effector network (e.g., PPARα signaling) to induce lipid metabolism disruption and oxidative stress. The research not only provides new therapeutic targets for NRASmut melanoma but also lays a theoretical foundation for the development of anti-tumor therapies based on lipid metabolism modulation.

Research Highlights

  1. Key Discovery: S6K2 is a survival dependency factor in MAPKi-resistant NRASmut melanoma, and its depletion triggers cell death by activating PPARα signaling and lipid peroxidation.
  2. Methodological Innovation: By combining PPARα agonists and PUFAs to mimic the effects of S6K2 depletion, the study offers new insights into developing low-toxicity anti-tumor drugs.
  3. Clinical Value: The research provides a new therapeutic strategy for NRASmut melanoma, particularly for patients who currently lack effective treatment options.

Other Valuable Information

This study also reveals, for the first time, the functional differences between S6K1 and S6K2 in melanoma, offering new perspectives on the biological functions of the S6K family. Additionally, the study suggests that inducing tumor cell death by modulating lipid metabolism may become an important direction for future cancer therapy.