Journal article
Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma
LK Smith, T Parmenter, M Kleinschmidt, EP Kusnadi, J Kang, CA Martin, P Lau, R Patel, J Lorent, D Papadopoli, A Trigos, T Ward, AD Rao, EJ Lelliott, KE Sheppard, D Goode, RJ Hicks, T Tiganis, KJ Simpson, O Larsson Show all
Nature Communications | Published : 2022
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 U..
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Grants
Awarded by National Health and Medical Research Council
Funding Acknowledgements
We thank the following Peter MacCallum Cancer Centre core facilities: Victorian Centre for Functional Genomics (VCFG), Molecular Genomics, Flow Cytometry and the Centre for Advanced Microscopy and Histology. The VCFG (K.J.S.) is funded by the Australian Cancer Research Foundation (ACRF), the Australian Phenomics Network (APN) through funding from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program and the Peter MacCallum Cancer Centre Foundation. We thank Daniel Thomas, Jennii Luu, Kate Gould and Piyush Madhamshettiwar from the VCFG for technical and analytical assistance with the genome-wide RNAi screen. We thank Dr Gisela Mir Arnau from Molecular Genomics for technical assistance with RNAseq. We also thank Rachael Walker and Susan Jackson from the Translational Research Lab and Alison Slater from the Molecular Oncology Lab for assisting in the in vivo studies. This work was supported by the Peter MacCallum Cancer Foundation and grants from the National Health and Medical Research Council of Australia (#1053792 and #1106576), the Cancer Council Victoria (APP1184894) and the CASS Foundation (#8539). A.R., P.L., R.P. and E.L. were supported by doctoral scholarships from the University of Melbourne and Cancer Therapeutics Cooperative Research Centre.