Despite the success of therapies targeting oncogenes in cancer, clinical outcomes appear to be limited by a drug adaptation and tolerance phase where initial pathway inhibition induces oncogenic network rewiring to allow cell survival 1. This rewiring precedes acquired resistance and thus represents an opportunity to prolong responses and prevent or delay resistance. Metabolic adaptation in response to MAPK pathway inhibition is well established in melanoma, and several metabolic vulnerabilities including glycolysis, oxidative phosphorylation and glutaminolysis have been linked with therapeutic response, adaptation and resistance 2-5. To examine how therapy reprograms metabolism we performed a genome-wide RNAi screen in melanoma cells following BRAF inhibition in the therapeutic adaptation phase prior to acquired resistance. This approach uncovered mRNA transport and translation, including RNA binding kinase UHMK1, as a critical regulator of metabolic responses to BRAF inhibition. Depletion of UHMK1 enhanced BRAF inhibitor sensitivity, synergistically suppressing glycolysis, proliferation, and viability, whilst analysis of mitochondrial metabolism revealed reduced spare respiratory capacity, ATP production and glutamine dependency. Together this data identifies a multifaceted role for UHMK1 in metabolic responses to BRAF inhibition. Mechanistically, polysome profiling and de novo protein synthesis assays revealed selective translation of mRNA encoding metabolic enzymes in cells adapting to BRAF inhibition, and critically, we show this is UHMK1 dependent. Moreover, we demonstrate UHMK1 interacts with mRNA encoding these enzymes, and regulates their nuclear-cytoplasmic transport. Our data suggests UHMK1 regulates therapy-induced metabolic adaptation by controlling the abundance of metabolic enzymes through the export and translation of the mRNA that encode them. We propose this pathway is an attractive therapeutic target to improve efficacy of MAPK pathway inhibitors by targeting the process of adaptation itself, rather than the outcome, as a next generation combination therapy.