Metabolism alterations accompany the invasive phenotype of melanoma cells resistant to BRAF/MEK inhibitors.

Abstract

Mutations in the BRAF (B-raf serine-threonine-protein kinase) gene occur in the majority of melanoma patients and significantly contribute to the progression of the disease. One of the most commonly used methods for treating melanoma is the use of BRAF and MEK (mitogen-activated protein kinase kinase) inhibitors. Unfortunately, resistance to treatment quickly develops in most patients. Therefore, an exhaustive understanding of the molecular basis of this resistance is crucial. We developed two melanoma cell lines resistant to vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), which we previously characterized as highly invasive. Because cancer cells acquiring resistance may undergo significant metabolic changes, we investigated these processes in the obtained melanoma double-resistant cells. These cells exhibit increased glycolysis and elevated caveolin 1 levels, which contribute to their increased invasiveness. The mitochondria present in the peripheral region of the resistant cells are more functional than those present in the same region of control cells. Resistant cells also form more lipid droplets, but they are smaller than in control cells. Cholesterol ester level is reduced in resistant cells, while free cholesterol level is elevated. Moreover, resistant cells exhibit reduced lipolysis rate and expression of proteins regulating this process. In summary, the obtained results suggest that the purpose of metabolic changes present in melanoma cells resistant to BRAF/MEK inhibitors is mainly to support the significantly increased invasiveness of these cells.