@article{084d8994f074419fbed146ff5a36394c,
title = "Codon-specific translation reprogramming promotes resistance to targeted therapy",
abstract = "Reprogramming of mRNA translation has a key role in cancer development and drug resistance(1). However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation(2,3). Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U-34) tRNA (U-34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF(V600E) oncogene and by resistance to targeted therapy in melanoma. We show that BRAF(V600E)-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U-34 enzymes. Mechanistically, U-34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1 alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U-34 enzymes and HIF1 alpha. Together, these results demonstrate that U-34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.",
keywords = "IMPROVED SURVIVAL, TRANSFER-RNAS, HUMAN CANCER, MELANOMA, VEMURAFENIB, INHIBITION, CELLS, MUTATIONS, RIBOSOME, KINASE",
author = "Francesca Rapino and Sylvain Delaunay and Florian Rambow and Zhaoli Zhou and Lars Tharun and {De Tullio}, Pascal and Olga Sin and Kateryna Shostak and Sebastian Schmitz and Jolanda Piepers and Bart Ghesquiere and Latifa Karim and Benoit Charloteaux and Diane Jamart and Alexandra Florin and Charles Lambert and Andree Rorive and Guy Jerusalem and Eleonora Leucci and Michael Dewaele and Marc Vooijs and Leidel, {Sebastian A.} and Michel Georges and Marianne Voz and Bernard Peers and Reinhard Buttner and Jean-Christophe Marine and Alain Chariot and Pierre Close",
year = "2018",
month = jun,
day = "28",
doi = "10.1038/s41586-018-0243-7",
language = "English",
volume = "558",
pages = "605--609",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7711",
}