Metastasis requires cancer cells to undergo poorly-understood metabolic changes1-3.,We found that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in Monocarboxylate Transporter 1 (MCT1) function.,In vivo isotope tracing in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumor lactate in efficient metastasizers.,Efficient metastasizers had higher MCT1 levels and MCT1 inhibition reduced lactate uptake.,MCT1 inhibition had little effect on primary subcutaneous tumor growth but depleted circulating melanoma cells and reduced metastatic disease burden in patient-derived xenografts and in mouse melanomas.,MCT1 inhibition suppressed the oxidative pentose phosphate pathway and increased ROS levels.,Anti-oxidants blocked the effect of MCT1 inhibition on metastasis.,MCT1high and MCT1−/low cells from the same melanomas had similar capacities to form subcutaneous tumors, but MCT1high cells formed more metastases after intravenous injection.,Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend upon MCT1 to manage oxidative stress.
Most melanoma patients with BRAFV600E positive tumors respond well to a combination of BRAF kinase and MEK inhibitors.,However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment.,For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets.,Cellular metabolism is such a promising new target line: mutant BRAFV600E has been shown to affect the metabolism.,Time course experiments and a series of western blots were performed in a panel of BRAFV600E and BRAFWT/NRASmut human melanoma cells, which were incubated with BRAF and MEK1 kinase inhibitors. siRNA approaches were used to investigate the metabolic players involved.,Reactive oxygen species (ROS) were measured by confocal microscopy and AZD7545, an inhibitor targeting PDKs (pyruvate dehydrogenase kinase) was tested.,We show that inhibition of the RAS/RAF/MEK/ERK pathway induces phosphorylation of the pyruvate dehydrogenase PDH-E1α subunit in BRAFV600E and in BRAFWT/NRASmut harboring cells.,Inhibition of BRAF, MEK1 and siRNA knock-down of ERK1/2 mediated phosphorylation of PDH. siRNA-mediated knock-down of all PDKs or the use of DCA (a pan-PDK inhibitor) abolished PDH-E1α phosphorylation.,BRAF inhibitor treatment also induced the upregulation of ROS, concomitantly with the induction of PDH phosphorylation.,Suppression of ROS by MitoQ suppressed PDH-E1α phosphorylation, strongly suggesting that ROS mediate the activation of PDKs.,Interestingly, the inhibition of PDK1 with AZD7545 specifically suppressed growth of BRAF-mutant and BRAF inhibitor resistant melanoma cells.,In BRAFV600E and BRAFWT/NRASmut melanoma cells, the increased production of ROS upon inhibition of the RAS/RAF/MEK/ERK pathway, is responsible for activating PDKs, which in turn phosphorylate and inactivate PDH.,As part of a possible salvage pathway, the tricarboxylic acid cycle is inhibited leading to reduced oxidative metabolism and reduced ROS levels.,We show that inhibition of PDKs by AZD7545 leads to growth suppression of BRAF-mutated and -inhibitor resistant melanoma cells.,Thus small molecule PDK inhibitors such as AZD7545, might be promising drugs for combination treatment in melanoma patients with activating RAS/RAF/MEK/ERK pathway mutations (50% BRAF, 25% NRASmut, 11.9% NF1mut).,The online version of this article (doi:10.1186/s12943-017-0667-y) contains supplementary material, which is available to authorized users.