Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer.

Mutant KRAS-driven control of protein synthesis remains poorly defined. Here, we define KRAS-dependent translational programs and their acute remodeling upon KRAS inhibition. We find that mutant KRAS controls the translation of a subset of mRNAs and affects the production of proteins of the mRNA translation apparatus. Interestingly, these specific subsets of mRNAs have short, weakly folded 5'UTRs and harbor low folding energy consensus RNA sequences. We observe ribosome accumulation on selective mRNAs. Our findings clarify the indispensable role of mutant KRAS in regulating mRNA translation, setting it apart from the other previously known mechanisms that depend on mTOR and EIF4E-EIF4A signals. Our findings uncover a mechanism by which mutant KRAS selectively uncouples the translation of mRNAs for protein synthetic machinery from the broader mRNA pool, redefining our understanding of the oncogenic regulation of mRNA translation in cancer.