KRAS-mediated regulation of mRNA translation program

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.

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Kamini Singh is a “cancer biologist” by training and has expertise in studying the “genetics and molecular basis of cancer progression”. She joined the faculty of Albert Einstein College of Medicine at the Department of Molecular Pharmacology in 2021 after completing her Ph.D. from National Center for Cell Science (India), postdoctoral training at Lerner Research Institute (USA), and research tenure as a Senior Scientist at Memorial Sloan Kettering Cancer Center (USA). During her research tenure, she has studied the function of tumor suppressors and oncogenes in signaling pathways using various cancer models including pancreatic cancer, breast cancer, melanoma, prostate cancer, leukemia, and lymphoma. She has published her key research findings in Nature, Cancer Research, Cancers, Journal of Experimental Medicine, Oncogene, and Blood. Her research group at Albert Einstein Medical College is committed to exploring the intricate mechanisms of mRNA translation and its critical role in cancer progression, metastasis, and immune response, using state-of-the-art technologies. Her team investigates the dynamics of translation start sites, identifying neo-antigens generated through translation, and characterizing the functional proteomes in cancer. Their aim is to identify vital biomarkers and design revolutionary new therapeutics that target specific mRNA translation programs and immune responses in cancer.