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Clin Cancer Res. 2019 Aug 2. doi: 10.1158/1078-0432.CCR-19-0253. [Epub ahead of print]

A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors.

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Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Surgery, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.



Treatment of BRAFV600E -mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi.


By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre- and on-treatment tumor specimens.


Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPARα-mediated and carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAFV600E -mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in vivo.


Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAFV600E -mutant melanoma.

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