 Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanomaLorey K. Smith (),
Tiffany Parmenter,
Margarete Kleinschmidt,
Eric P. Kusnadi,
Jian Kang,
Claire A. Martin,
Peter Lau,
Riyaben Patel,
Julie Lorent,
David Papadopoli,
Anna Trigos,
Teresa Ward,
Aparna D. Rao,
Emily J. Lelliott,
Karen E. Sheppard,
David Goode,
Rodney J. Hicks,
Tony Tiganis,
Kaylene J. Simpson,
Ola Larsson,
Benjamin Blythe,
Carleen Cullinane,
Vihandha O. Wickramasinghe,
Richard B. Pearson and
Grant A. McArthur ()
Nature Communications, 2022, vol. 13, issue 1, 1-21 Abstract: 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. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28705-x Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-022-28705-x Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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