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

Abstract

Purpose: Treatment of BRAF V600E -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.Experimental Design: 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 ontreatment tumor specimens.Results: Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPARa-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 BRAF V600E -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.Conclusions: Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAF V600E -mutant melanoma.

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…Plasticity of the melanoma cell phenotype is often driven by changes in the tumor microenvironment, such as hypoxia, pH, and nutrient supply [ 103 , 104 ]. BRAF inhibitor treatment is also associated with a change in the metabolic profile of cells, with a shift towards more mitochondrial respiration and the formation of reactive oxygen species [ 103 , 105 , 106 , 107 , 108 , 109 , 110 ].…”

Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

“…Comparative analyses between melanoma cells and benign nevi show that carnitine palmitoyltransferase 2 (CPT) 2, an enzyme critical for translocation of long-chain Fas, is one of the most upregulated gene in melanoma (100). Interestingly, melanoma cells treated with MAPKi showed an increase of CD36 levels and fatty acid oxidation (FAO) levels in a manner dependent by peroxisome proliferator-activated receptor (PPAR-α) and CPT1A (101). Of note, the sustained FAO is essential for survival of BRAF V600E -mutant melanoma cells, under the MAPKiinduced metabolic stress prior to acquiring drug resistance (101).…”

Overcoming Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutated Tumours

“…us, the concomitant inhibition of CPT1A, glycolysis, and MAPK synergistically inhibited tumour cell growth in vitro and in BRAF V600E -mutated melanoma mouse models [184].…”

“…AMPK phosphorylates and inactivates acetyl-CoA carboxylase, which impedes fatty acid synthesis and promotes lipid utilization by beta-oxidation in the mitochondria (Figure 2(d)) [183]. In fact, a recent study by Aloia has shown that upregulation of fat oxidation plays a role in the adaptive response to MAPK inhibition [184]. Particularly, the pharmacological blockade of CPT1A (the rate-limiting step for fat oxidation) reactivated glycolysis in MAPKitreated melanoma cells.…”