Mutant KRAS-Driven Selective mRNA Translation Reveals Mechanisms and Therapeutic Vulnerabilities in Cancer

mRNA translation is highly regulated and rapidly controls the functional proteome in response to physiological cues in health and disease. Mutant KRAS signals to ERKs intersect with the mTOR and EIF4E-EIF4F complex, thereby influencing cap-dependent mRNA translation to promote tumorigenesis. With recent clinical advances in KRAS-targeted therapies, it is important to understand the changes in the mRNA translational landscape and its role in cellular adaptations in response to mutant KRAS-targeted therapies. We discover that mutant KRAS controls the translation of a subset of mRNAs and affects the protein production of the translation apparatus. Interestingly, these specific subsets of mRNAs have short, weakly folded 5’UTRs, or harbor low folding energy consensus RNA sequences. This mutant KRAS-dependent mechanism differs from mTOR and EIF4E-EIF4F regulation, which governs cap-dependent translation of mRNAs with highly structured, GC-rich 5' UTRs or TOP motifs. Our findings clarify the unique and indispensable role of mutant KRAS in regulating mRNA translation, distinctly setting it apart from the mTOR and EIF4E-EIF4A-dependent mechanism. Our findings uncover a novel mechanism by which mutant KRAS selectively uncouples the mRNA translation of the translation machinery from the broader mRNA pool, redefining our understanding of the oncogenic regulation of mRNA translation in cancer.