Cell-surface receptors guide antisense therapy to mutant KRAS in pancreatic cancer cells
Antisense oligonucleotides (ASOs) have been proposed as a therapeutic approach to shut down the production of faulty proteins in a wide variety of diseases, including cancer. In a study published in the Journal of Cell Biology (JCB), researchers at the Cancer Research UK Scotland Institute and the University of Glasgow identify a pathway by which ASOs enter cells and reach their targets,…
Cell-surface receptors CD44 and EPHA2 play a crucial role in guiding antisense therapy to mutant KRAS in pancreatic cancer cells. ASOs, short strands of DNA, are designed to bind to specific mRNA sequences and prevent the production of faulty proteins. In a study published in the Journal of Cell Biology, researchers found that cET-ASOKRas, an ASO targeting mutant KRAS, enters cells through endocytosis after binding to CD44.
This initiates a signaling pathway that activates EPHA2, causing the ASOs to be taken up into endosomes and anchored near the nucleus. Once at the nucleus, the endosomal membranes become leaky, allowing the ASOs to enter the cytoplasm and reach their target mRNA. Inhibiting this pathway by deleting CD44 or EPHA2, or expressing EPHA2 mutants, prevents the ASOs from reducing KRAS levels and inhibiting tumor growth.
However, cells have a defense mechanism against this process. When endosomes near the nucleus become leaky, cells form stress granules that repair the endosome membrane. Blocking stress granule formation with a drug called ISRIB enhances the effectiveness of cET-ASOKRas in suppressing KRAS production. CD44 and EPHA2 are highly expressed in aggressive pancreatic cancers, which may make them potential targets for enhancing the delivery of therapeutic molecules like cET-ASOKRas to aggressive tumors.
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