A codon-defined translational program promotes RAS-driven cancer progression and drug resistance

Codon usage affects translation efficiency, yet how oncogenic signaling exploits codon-selective translation remains largely unknown. Here, we uncover a codon-defined translational program as a functional output of RAS-MAPK signaling. Through integrated translational analyses, we identify a codon-defined module of genes enriched for the rare arginine codon CGA, whose translation is specifically promoted by RAS activation. These genes encode key regulators of ribosome biogenesis, RNA splicing, and cell cycle control, many previously regarded as “undruggable” drivers of tumor progression and therapeutic resistance. Mechanistically, RSK (a RAS effector kinase)-mediated phosphorylation of METTL13 at S267 enhances its stability and catalytic activity toward eEF1A K55 dimethylation, accelerating CGA decoding. Disruption of this phospho-methyl relay selectively impairs CGA translation, suppresses RAS-driven tumor growth, and overcomes both intrinsic and acquired resistance to RAS pathway inhibitors. Therapeutically, combining METTL13 inhibition with RAS signaling inhibitors achieves superior tumor suppression compared with current clinical combinations of kinase inhibitors. By defining a codon-based translational mechanism, our study reveals a previously unrecognized layer of translation-level signal interpretation, introduces a “one-handle-multiple-effector” strategy to enhance the durability of targeted cancer therapies, and establishes METTL13 as a mechanistically defined and targetable node in malignant translation control.