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Open AccessArticle

Metabolic Reprogramming in Metastatic Melanoma with Acquired Resistance to Targeted Therapies: Integrative Metabolomic and Proteomic Analysis

1
Laboratory of Human Anatomy & Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons, 7000 Mons, Belgium
2
Laboratory of Human Biology & Toxicology, Faculty of Medicine and Pharmacy, University of Mons, 7000 Mons, Belgium
3
Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet (ULB), 1000 Brussels, Belgium
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(5), 1323; https://doi.org/10.3390/cancers12051323
Received: 23 April 2020 / Revised: 18 May 2020 / Accepted: 19 May 2020 / Published: 22 May 2020
Treatments of metastatic melanoma underwent an impressive development over the past few years, with the emergence of small molecule inhibitors targeting mutated proteins, such as BRAF, NRAS, or cKIT. However, since a significant proportion of patients acquire resistance to these therapies, new strategies are currently being considered to overcome this issue. For this purpose, melanoma cell lines with mutant BRAF, NRAS, or cKIT and with acquired resistances to BRAF, MEK, or cKIT inhibitors, respectively, were investigated using both 1H-NMR-based metabonomic and protein microarrays. The 1H-NMR profiles highlighted a similar go and return pattern in the metabolism of the BRAF, NRAS, and cKIT mutated cell lines. Indeed, melanoma cells exposed to mutation-specific inhibitors underwent metabolic disruptions following acute exposure but partially recovered their basal metabolism in long-term exposure, most likely acquiring resistance skills. The protein microarrays inquired about the potential cellular mechanisms used by the resistant cells to escape drug treatment, by showing decreased levels of proteins linked to the drug efficacy, especially in the downstream part of the MAPK signaling pathway. Integrating metabonomic and proteomic findings revealed some metabolic pathways (i.e., glutaminolysis, choline metabolism, glutathione production, glycolysis, oxidative phosphorylation) and key proteins (i.e., EPHA2, DUSP4, and HIF-1A) as potential targets to discard drug resistance. View Full-Text
Keywords: metastatic melanoma; targeted therapies; resistance to drugs; metabonomics; proteomics; metabolic switch; cancer metabolic reprogramming metastatic melanoma; targeted therapies; resistance to drugs; metabonomics; proteomics; metabolic switch; cancer metabolic reprogramming
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Soumoy, L.; Schepkens, C.; Krayem, M.; Najem, A.; Tagliatti, V.; Ghanem, G.E.; Saussez, S.; Colet, J.-M.; Journe, F. Metabolic Reprogramming in Metastatic Melanoma with Acquired Resistance to Targeted Therapies: Integrative Metabolomic and Proteomic Analysis. Cancers 2020, 12, 1323.

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