BRAF activation by metabolic stress promotes glycolysis sensitizing NRAS^Q61-mutated melanomas to targeted therapy

Area of Science:

• Oncology
• Cancer Metabolism
• Melanoma Research

Background:

• NRAS-mutated melanoma lacks targeted therapies.
• Metabolic reprogramming is a key hallmark of cancer, but its role in NRAS-mutated melanoma is unclear.
• Understanding NRAS oncogene's contribution to metabolic alterations is crucial for developing new treatments.

Purpose of the Study:

• To investigate the metabolic dependencies of NRAS-mutated melanoma.
• To identify novel therapeutic strategies targeting metabolic pathways in NRAS-mutated melanoma.
• To explore the combined effect of metabolic stress and sorafenib in NRAS-mutated melanoma.

Main Methods:

• Analysis of metabolic reprogramming in NRAS-mutated melanoma cells.
• Investigating the switch in signaling pathways (CRAF to BRAF) under glucose deprivation.
• Utilizing in vivo models, including patient-derived xenografts, for treatment efficacy studies.

Main Results:

• NRAS-mutated melanoma exhibits specific metabolic vulnerabilities.
• Glucose deprivation induces a switch to BRAF signaling, sustaining glucose metabolism via PFKFB2/PFKFB3 and PFK1.
• Combined treatment with 2-deoxy-D-glucose (2-DG) and sorafenib significantly inhibited tumor growth in vivo.

Conclusions:

• NRAS oncogenes contribute to metabolic rewiring in melanoma.
• Targeting glycolysis with inhibitors like 2-DG, combined with sorafenib, offers a promising therapeutic approach for NRAS-mutated melanoma.
• This study provides a proof-of-principle for combination therapy in this challenging cancer type.