Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most mutated genes (up to 25%) linked to cancer. KRAS is frequently mutated in pancreatic cancer (PDAC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC) and as such, it is an attractive therapeutic target. Despite the significant advances in KRAS biology and drugs targeting mutant KRAS activity, there remains a gap in the knowledge of KRAS-driven mRNA translation and regulation of immune response during the progression of cancer and metastasis. We show that mutant KRAS drives specific mechanisms of translational control to support cancer growth. We have utilized the technology of ribosome footprinting combined with advanced sequencing methodology to define the translation landscape affected by a specific inhibitor of KRAS, sotorasib that targets G12C mutant KRAS activity. We show that acute treatment of sotorasib inhibits the translation of key oncogenic proteins including MYC and MYC targets. KRAS (G12C) inhibition profoundly affects the translation of ribosomal proteins and translation elongation factors. G12C mutant KRAS remarkably affects the translation of proteins involved in metabolism, reactive oxygen species, and DNA repair pathways. Moreover, these translational changes are mediated through specific RNA motifs and RNA binding proteins. In summary, our study defines the KRAS (G12C) specific regulation of translation and provides the mechanism of KRAS (G12C) mediated regulation of cancer proteome.<\/p>\n
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