Metastatic uveal melanoma (UM) has a very poor prognosis and no effective therapy.,Despite remarkable advances in treatment of cutaneous melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase inhibitors, and immune-based therapy.,We assessed two sets of oxidative phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types.,An OxPhos inhibitor was used to characterize differential metabolic programming of highly metastatic monosomy 3 (M3) UM.,Seahorse analysis and global metabolomics profiling were done to identify metabolic vulnerabilities.,Analyses of UM TCGA data set were performed to determine expressions of key OxPhos effectors in M3 and non-M3 UM.,We used targeted knockdown of succinate dehydrogenase A (SDHA) to determine the role of SDHA in M3 UM in conferring resistance to OxPhos inhibition.,We identified UM to have among the highest median OxPhos levels and showed that M3 UM exhibits a distinct metabolic profile.,M3 UM shows markedly low succinate levels and has highly increased levels of SDHA, the enzyme that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) succinate.,We showed that SDHA-high M3 UM have elevated expression of key OxPhos molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are resistant to OxPhos antagonism, which can be reversed by SDHA knockdown.,Our study has identified a critical metabolic program within poor prognostic M3 UM.,In addition to the heightened mitochondrial functional capacity due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is reversible with targeted treatment.
Control of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance.,Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells.,Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance.,PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo.,This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells.,PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment.,Similarly to PDGFRα inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I.,These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition.,The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression.,These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors.