RNA binding kinase UHMK1 regulates therapy induced metabolic adaptation in BRAFV600 melanoma

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by drug adaptation and resistance. BRAF inhibition in melanoma results in multiple cellular adaptations that precede resistant disease, including altered metabolism. Here, we use a genome-wide RNAi screen to identify mRNA transport and translation as regulators of metabolic response and adaptation following BRAF inhibition in melanoma cells. Mechanistically, we demonstrate the RNA binding kinase UHMK1 interacts with mRNAs that encode metabolic proteins and selectively controls their transport and translation. Importantly, genetic inactivation of UHMK1 delays resistance to BRAF and MEK combination therapy in vivo. Our data support a model wherein selective mRNA transport and translation is activated in response to therapeutic stress and contributes to metabolic adaptation underpinning therapeutic response. Inhibition of this process may extend efficacy of targeted therapies in oncogene driven cancers that rely on RAS-MAPK signaling networks.