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Background  BRAF inhibitors, such as vemurafenib, have shown efficacy in  BRAF -mutant melanoma treatment but acquired-resistance invariably develops. Unveiling the potential vulnerabilities associated with vemurafenib resistance could provide rational strategies for combinatorial treatment.    Methods  This work investigates the metabolic characteristics and vulnerabilities of acquired resistance to vemurafenib in three generated  BRAF -mutant human melanoma cell clones, analysing metabolic profiles, gene and protein expression in baseline and nutrient withdrawal conditions. Preclinical findings are correlated with gene expression analysis from publicly available clinical datasets.    Results  Two vemurafenib-resistant clones showed dependency on lipid metabolism and increased prostaglandin E2 synthesis and were more responsive to vemurafenib under EGFR inhibition, potentially implicating inflammatory lipid and EGFR signalling in ERK reactivation and vemurafenib resistance. The third resistant clone showed higher pyruvate-carboxylase (PC) activity indicating increased anaplerotic mitochondrial metabolism, concomitant with reduced GLUT-1, increased PC protein expression and survival advantage under nutrient-depleted conditions. Prostaglandin synthase ( PTGES ) expression was inversely correlated with melanoma patient survival. Increases in  PC  and  PTGES  gene expression were observed in some patients following progression on BRAF inhibitors.    Conclusions  Altogether, our data highlight heterogeneity in metabolic adaptations during acquired resistance to vemurafenib in  BRAF -mutant melanoma, potentially uncovering key clinically-relevant mechanisms for combinatorial therapeutic targeting.

british journal of cancer

Increased inflammatory lipid metabolism and anaplerotic mitochondrial activation follow acquired resistance to vemurafenib in BRAF-mutant melanoma cells