Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma
Journal Title
Nature Communications
Publication Type
Research article
Abstract
Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.
Keywords
Humans; *Melanoma/drug therapy/genetics/metabolism; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local/drug therapy; Protein Kinase Inhibitors/pharmacology; *Proto-Oncogene Proteins B-raf/metabolism; RNA, Messenger/therapeutic use
Department(s)
Laboratory Research; Medical Oncology
PubMed ID
35232962
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-022-28705-x
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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