Article
Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma

Published in
Nature Cell Biology

Abstract
Why some melanomas escape MAPK-targeted therapy remains a clinical challenge. This study shows that valine aminoacyl-tRNA synthetase (VARS), a core enzyme of the tRNA charging machinery, is a critical driver of resistance. Melanoma cells that survived MAPK inhibitor treatment displayed elevated VARS expression and activity, together with enrichment of valine-containing proteins and their cognate tRNAs. VARS acts by selectively boosting translation of valine-rich transcripts, among them hydroxyacyl-CoA dehydrogenase (HADH), which fuels fatty acid oxidation. Depleting VARS re-sensitized resistant melanoma models to MAPK inhibitors both in vitro and in vivo, showing that altered tRNA charging directly contributes to metabolic adaptation and drug resistance.

Results

• MAPK inhibitor-resistant melanoma cells show higher VARS expression and activity.
• Resistant proteomes are enriched in valine-containing proteins and valine-codon-rich transcripts.
• VARS preferentially promotes translation of valine-enriched mRNAs rather than raising global protein output.
• VARS controls HADH, an enzyme essential for fatty acid oxidation.
• Resistant cells depend on fatty acid oxidation for survival under MAPK inhibition.
• VARS depletion lowers fatty acid oxidation and restores sensitivity to targeted therapy.
• HADH knockdown phenocopies VARS depletion, confirming the VARS-HADH axis sustains metabolic adaptation and resistance.

trna-charging-analysis-in-cancer-melanoma-therapy-resistance_1.png

Fig. 1. VARS-mediated tRNA charging drives translation of valine-rich metabolic genes and supports fatty-acid-oxidation-dependent therapy resistance in melanoma.

Conclusion

Valine-specific tRNA charging emerges from this work as a pivotal mechanism of melanoma adaptation to targeted therapy. Elevated VARS activity allows selective translation of valine-rich transcripts that maintain fatty acid oxidation and cell survival under MAPK inhibition. These findings broaden the known functions of aminoacyl-tRNA synthetases beyond canonical protein synthesis and highlight tRNA charging as a regulatory hub connecting translational control, metabolic reprogramming, and drug resistance. Targeting VARS could therefore offer a new route to overcome melanoma therapy resistance.

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