Acquired BRAFi Resistance Increases Melanoma Cell Sensitivity to Metabolic Targeting with Metformin
Abstract
Targeted inhibition of the MAPK pathway using BRAF inhibitors (BRAFi) represents a cornerstone of treatment for BRAFV600E-mutant melanoma. However, the rapid emergence of drug resistance remains a major clinical challenge. Mounting evidence indicates that therapy resistance is driven by both phenotypic plasticity and metabolic reprogramming. In this study, we investigated the molecular, phenotypic, and metabolic adaptations underlying acquired resistance to the BRAFi GSK2118436 in A375 melanoma cells. BRAFi-resistant cells (A375-R) displayed cross-resistance to additional BRAFi and MEK inhibitors and clear features of epithelial–mesenchymal transition (EMT), including E-cadherin decreased, vimentin increased, and inhibitor dependent’s spheroid compaction. Metabolic profiling suggests a shift toward mitochondrial oxidative phosphorylation (OXPHOS) dependency. Among multiple metabolic modulators evaluated, inhibitors of mitochondrial respiration—particularly metformin and antimycin A—selectively impaired viability, clonogenicity, and 3D growth of resistant cells. Importantly, while simultaneous BRAFi–metformin combination produced mostly antagonist effects, a sequential regimen (BRAFi followed by metformin) elicited additive/synergistic cytotoxicity in both 2D and 3D models. Collectively, these findings show that BRAFi resistance is driven by coordinated EMT and metabolic rewiring toward OXPHOS dependency and identify sequential metabolic targeting as an effective strategy to…
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