Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice

Area of Science:

• Oncology
• Metabolic Research
• Drug Resistance

Background:

• Melanoma rapidly develops resistance to vemurafenib, a key therapy for BRAFV600 mutant melanomas.
• Targeting metabolic shifts in resistant melanoma is promising, but the link between drug tolerance and metabolic plasticity is unexplored.

Purpose of the Study:

• To investigate how vemurafenib tolerance levels influence metabolic plasticity in BRAFV600E mutant melanoma.
• To identify distinct metabolic profiles associated with varying vemurafenib resistance levels.

Main Methods:

• Development of isogenic BRAFV600E vemurafenib-resistant (VemR) melanoma models with differential drug tolerances.
• Integrative analysis of metabolomic and transcriptomic data using metabolome, Mitoplate-S1, Seahorse, and RNA-seq.

Main Results:

• Both VemR models showed cross-resistance to MEK inhibitors but sensitivity to Wnt/β-catenin inhibitor ICG-001.
• ICG-001 treatment reversed vemurafenib sensitivity by reducing MITF, ABCB5, phospho-ERK1/2, and mitochondrial respiration.
• β-catenin signaling activated the TCA cycle/OXPHOS in high-tolerance cells and the pentose phosphate pathway in low-tolerance cells, both inhibited by ICG-001.

Conclusions:

• Wnt/β-catenin signaling plays a crucial role in vemurafenib resistance-induced metabolic plasticity.
• Drug tolerance thresholds directly drive specific metabolic pathway shifts in resistant melanoma, enabling targeted therapy selection.