Codon-specific translation reprogramming promotes resistance to targeted therapy.

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 (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.

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