Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma

Brummer C, Faerber S, Bruss C, Blank C, Lacroix R, Haferkamp S, Herr W, Kreutz M, Renner K (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Cancer Letters Elsevier

Book Volume: 442

Pages Range: 453-463

DOI: 10.1016/j.canlet.2018.11.018

Abstract

Tumors, including melanomas, frequently show an accelerated glucose metabolism. Mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF), detected in about 50% of all melanomas, result in further enhancement of glycolysis. Therefore anti-metabolic substances might enhance the impact of RAF inhibitors. We have identified the two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and lumiracoxib being able to restrict energy metabolism in human melanoma cells by targeting lactate release and oxidative phosphorylation (OXPHOS). In combination with the RAF inhibitor vemurafenib strong synergism was observed: Diclofenac as well as lumiracoxib increased the anti-glycolytic impact of vemurafenib and prevented RAF-inhibitor induced metabolic reprogramming towards OXPHOS. Consequently, both NSAIDs sensitized melanoma cells to vemurafenib triggered proliferation arrest and enhanced the anti-tumor effect of RAF inhibitors from cytostatic to cytotoxic. Furthermore the addition of NSAIDs delayed the onset of RAF inhibitor resistance, most likely by counteracting the upregulation of MITF. Our data suggest that selected NSAIDs could be a promising combination partner for MAPK pathway inhibitors for the treatment of BRAFV600E mutated melanomas.

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Netherlands Cancer Institute (NKI) NL Netherlands (NL)

How to cite

APA:

Brummer, C., Faerber, S., Bruss, C., Blank, C., Lacroix, R., Haferkamp, S.,... Renner, K. (2019). Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma. Cancer Letters, 442, 453-463. https://doi.org/10.1016/j.canlet.2018.11.018

MLA:

Brummer, Christina, et al. "Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma." Cancer Letters 442 (2019): 453-463.

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