Journal
MOLECULAR ONCOLOGY
Volume 10, Issue 1, Pages 73-84Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.molonc.2015.08.003
Keywords
BRAF; Resistance; Melanoma; Metabolism; Glutaminolysis
Categories
Funding
- Cancer Research UK Manchester Institute [C5759/A12328]
- Cancer Research UK [A17240]
- Wellcome Trust [WT1005X]
- Cancer Research UK Beatson Institute [12477]
- Cancer Research UK [19279, 22902, 18278, 17240] Funding Source: researchfish
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BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first line setting. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.
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