Abstract
BackgroundBRAF 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.MethodsThis 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.ResultsTwo 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.ConclusionsAltogether, 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.
Highlights
BRAF inhibitors, such as vemurafenib, have shown efficacy in BRAF-mutant melanoma treatment but acquiredresistance invariably develops
BRAF-mutant melanoma cell clones with acquired resistance to vemurafenib show heterogeneous metabolic profiles Three independent clones resistant to vemurafenib were generated from the parental melanoma cell line A375 as described in the Methods section
Previous findings related to metabolic mechanisms of acquired resistance in melanoma report an increased dependency on mitochondrial metabolism either through PC19 or glutamine metabolism,[32] and increased glycolytic metabolism.[33]
Summary
BRAF inhibitors, such as vemurafenib, have shown efficacy in BRAF-mutant melanoma treatment but acquiredresistance invariably develops. The mitogen-activated protein kinase (MAPK) pathway, known as the RAS/RAF/MEK/ERK pathway is involved in the control of cell growth, differentiation and survival in normal physiological conditions.[1,2] The activity of the proteins involved in this signalling pathway is regulated by a phosphorylation cascade initiated by the activation of tyrosine kinase membrane receptors such as the epidermal growth factor receptor (EGFR) Abnormalities in this kinase cascade play a critical role in the development and progression of cancer, promoting uncontrolled cell replication, evasion of apoptosis, and the ability to invade and metastasise.[2,3]. 50% of melanomas harbour activating BRAF mutations and over 90% of these give rise to the mutant protein
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