Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors

Cell Death & Disease
Raeeka KhamariJérome Kluza

Abstract

Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistan...Continue Reading

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Methods Mentioned

BETA
biopsies
biopsy
xenograft
NMR
flow cytometry
Fluorescences
PCR
ubiquitination
FCS
FACS

Software Mentioned

Analyst
GraphPad
Scan
GraphPad Prism®
QIAGEN
PET
Bruker TopSpin
KnowItAll®

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