Methylated eEF1A selectively decodes mRNA to shape cancer proteomes

Although mRNA decoding efficiency influences protein synthesis, it remains unknown whether the translation elongation machinery harbours intrinsic mechanisms that selectively modulate codon decoding to shape proteomes. Here we show that METTL13-catalysed dimethylation of the elongation factor eEF1A at lysine 55 (eEF1AK55me2) enhances decoding of select codons, preferentially increasing pro-oncogenic protein synthesis to promote tumorigenesis and targeted therapy resistance. Proteomic profiling and single-molecule imaging reveal that eEF1AK55me2 increases decoding efficiency, particularly for under-represented codons with weak wobble-position base pairing. In cancer cells, METTL13 knockdown reduced translation of oncogenic mRNA enriched in eEF1AK55me2-dependent codons, including KRAS; synonymous recoding with eEF1AK55me2-independent codons reversed this effect. METTL13 loss inhibited the growth of KRASG12C inhibitor (sotorasib)-resistant lung adenocarcinoma syngeneic tumours and patient-derived xenografts. In relapsed autochthonous KRASG12C-driven lung adenocarcinoma, METTL13 ablation mitigated sotorasib resistance and significantly extended survival in vivo. Among patients receiving a KRASG12C inhibitor, inferred METTL13 activity was associated with inferior clinical response. These findings identify an eEF1AK55me2-mediated mRNA decoding mechanism promoting selective oncogenic protein synthesis and suggest METTL13 targeting may counteract KRAS-inhibitor resistance. The authors show that METTL13-mediated eEF1A K55 dimethylation enhances decoding of rare codons, boosting translation of oncogenic proteins including KRAS and promoting KRAS-inhibitor resistance in lung cancer.