Good news! Cancer is history (soon)!
"The lab ... has identified a new strategy for attacking treatment-resistant melanoma: inhibiting the gene S6K2. ...
the group took aim at melanomas with a mutation in the NRAS gene (abbreviated as NRASMUT melanoma).
NRASMUT melanoma accounts for about 30% of all melanoma cases, which has made it a priority of melanoma researchers. ...
The team tested their hypothesis in the lab by silencing the S6K2 gene, which successfully killed NRASMUT melanoma cell lines known to resist MAPK inhibition. Further analysis revealed that S6K2 inhibition killed these cancer cells by disrupting an important lipid metabolism process. ...
When they silenced S6K2, the team noticed that it had an effect on another gene called PPARα. After refining their understanding of PPARα’s effects on NRASMUT melanomas, the researchers capitalized on this finding by using a combination treatment of two compounds, fenofibrate (which activates PPARα) and DHA (also known as Omega-3), to successfully induce cell death in melanomas that were known to resist treatment with MAPK inhibitors. ..."
From the editor's summary and abstract:
"Editor’s summary
Oncogenic mutations in NRAS are relatively common in cutaneous melanomas. Although mutant NRAS drives tumor growth through MAPK signaling, MAPK inhibition is effective only in a minority of patients. Thus, additional treatments are needed for MAPK inhibitor–resistant melanomas harboring NRAS mutations.
Here, Lipchick et al. identified the ribosomal protein S6 kinase 2 (S6K2) as a potentially targetable therapeutic vulnerability of NRAS-mutant melanomas exhibiting resistance to MAPK inhibition. Knockdown of S6K2 triggered up-regulation of PPARα, accumulation of polyunsaturated fatty acids, and cell death in vitro.
Dual treatment with PPARα agonist and polyunsaturated fatty acids phenocopied the effects of S6K2 knockdown and reduced tumor growth in vivo. Together, these data identify S6K2 as a potential therapeutic target for MAPK inhibitor–resistant NRAS-mutant melanoma.
Abstract
Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant (NRASMUT) 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 NRASMUT 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 NRASMUT melanomas that are resistant to global MAPK pathway inhibitors."
Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor–resistant NRAS-mutant melanoma (no public access)
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