A fatty acid oxidation-dependent metabolic shift regulates the adaptation of BRAF-mutated melanoma to MAPK inhibitors
Treatment of BRAF-mutant melanomas with mitogen-activated protein kinase inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. A Clinical Cancer Research paper by the Krek/Kovacs group (IMHS) describes a metabolic shift in MAPKi-treated melanomas that might be exploited to prevent therapeutic resistance.
MAPK inhibition triggers molecular processes responsible for acquired resistance in melanoma. The Krek/Kovacs group identified the fatty acid transporter CD36 as a marker of transiently resistant and MAPKi-tolerant BRAFV600E melanoma cells. Furthermore, they describe a metabolic reprogramming that occurs during the initial phase of MAPKi treatment and is characterized by decreased glycolysis and increased fatty acid oxidation (FAO). Increased FAO is required for BRAFV600E-mutant melanoma cells to survive under MAPKi-induced metabolic stress prior to acquiring drug resistance. FAO inhibitors increase the glycolytic flux in untreated and MAPKi-treated melanoma cells as a compensatory mechanism to FAO inhibition. To exploit melanoma cells’ metabolic plasticity for therapeutic intervention, they propose a triple combination of MAPK, FAO, and glycolytic inhibitors as a novel treatment option to improve initial responses and to delay or prevent drug resistance in BRAF-mutated melanomas.
Link to the publication in "external page Clinical Cancer Research".