Fig. 9
Model summarising metabolic changes in sentitive versus resistant melanoma cells upon BRAF inhibition. a BRAFV600E, in addition to its well known effects on the cell cycle and anti-apoptosis, leads to upregulation of glucose uptake and LDH-A, promoting aerobic glycolysis and cell growth. Moreover, activation of BRAF, leads to the induction of genes involved in antioxidant defense. b Upon treatment with BRAF inibitors, or other MEK/ERK pathway inhibitors, glycolysis is inhibited. Changes in metabolic fluxes through the TCA cycle together with the inhibition of the transcription of antioxidant genes, induce ROS. The increasing levels of ROS activate PDKs, which in turn inactivate PDH, thus reducing pyruvate use in the TCA cycle, which in a negative regulatory loop, inhibit further ROS production. c In BRAF inhibitor resistance, the MAPK pathway is reactivated by compensatory mechanisms and as a consequence glycolysis and antioxidant-defence genes are reactivated. Glycolysis produces ATP, nucleotides (via the pentose phosphate pathway (PPP)), NADPH (for antioxidant defense via PPP) and amino acids. The cells become addicted to an oxidative metabolism with glutamine (Gln) feeding anaplerotically into the TCA cycle to produce NADH, amino acids, ATP (via Oxphos), fatty acids (via AcetylCoA) and ROS. These ROS can be kept in check by NADPH, which is produced by the PPP and by antioxidant gene transcription downstream of the RAS/RAF/MEK/ERK pathway. At need, PDKs are activated by ROS and PDH is inhibited. This prevents pyruvate from entering the TCA and ROS to reach toxic levels. d In BRAF inhibitor resistance of melanoma, pharmacological inhibition of PDKs releases the brake on pyruvate entry into the TCA and causes unchecked pyruvate use, associated with an increase in ROS production. This increase in ROS tilts the balance towards cell death. Thus potent nonomolar PDK inhibitors could efficiently reduce the viability of BRAFi-resistant cells or might prevent or delay BRAFi resistance