Codon-specific translation reprogramming promotes resistance to targeted therapy

Nature. 2018 Jun;558(7711):605-609. doi: 10.1038/s41586-018-0243-7. Epub 2018 Jun 20.


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 translation2,3. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 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 U34 enzymes. Mechanistically, U34 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 HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Codon / drug effects
  • Codon / genetics*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Melanoma / pathology
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phosphorylation
  • Protein Biosynthesis* / drug effects
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Transfer / chemistry
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism
  • Signal Transduction
  • Transcriptional Elongation Factors
  • Uridine / chemistry
  • Uridine / genetics
  • Uridine / metabolism
  • Vemurafenib / pharmacology
  • Vemurafenib / therapeutic use
  • Zebrafish / genetics


  • Carrier Proteins
  • Codon
  • Elp1 protein, human
  • RNA, Messenger
  • Transcriptional Elongation Factors
  • Vemurafenib
  • RNA, Transfer
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins B-raf
  • Uridine