Inhibition of fatty acid synthesis induces differentiation and reduces tumor burden in childhood neuroblastoma

Abstract

Many metabolic pathways, including lipid metabolism, are rewired in tumors tosupport energy and biomass production and to allow adaptation to stressful en-vironments. Neuroblastoma is the second deadliest solid tumor in children. Ge-netic aberrations, as the amplification of theMYCN-oncogene, correlate stronglywith disease progression. Yet, there are only a few molecular targets successfullyexploited in the clinic. Here we show that inhibition of fatty acid synthesis led toincreased neural differentiation and reduced tumor burden in neuroblastomaxenograft experiments independently ofMYCN-status. This was accompaniedby reduced levels of the MYCN or c-MYC oncoproteins and activation of ERKsignaling. Importantly, the expression levels of genes involved inde novofattyacid synthesis showed prognostic value for neuroblastoma patients. Our findingsdemonstrate that inhibition ofde novofatty acid synthesis is a promising pharma-cological intervention strategy for the treatment of neuroblastoma indepen-dently ofMYCN-status.