Cell-surface receptors guide antisense therapy to mutant KRAS in pancreatic cancer cells

Scientists at the Cancer Research UK Scotland Institute and the University of Glasgow, working with Ionis Pharmaceuticals, have mapped how an antisense oligonucleotide (ASO) called cET-ASO KRas enters pancreatic cancer cells and reaches its target. The study, published in the Journal of Cell Biology, focuses on mutant KRAS, a protein that drives several cancers including pancreatic ductal adenocarcinoma.

ASOs are short DNA strands designed to bind specific messenger RNAs and trigger their degradation, preventing production of disease-causing proteins. While ASOs enter cells through endocytosis, the precise route and how they find their mRNA targets have been unclear.

The researchers found that cET-ASO KRas binds to the cell-surface receptor CD44, which activates a second receptor, EPHA2. This triggers uptake of the ASO into endosomes, and EPHA2 then anchors those endosomes near the cell nucleus where most mRNA is produced.

Near the nucleus, the endosomal membranes become leaky, allowing the ASO to escape into the cytoplasm and encounter mutant KRAS mRNA. Deleting CD44 or EPHA2, or using EPHA2 mutants that cannot anchor endosomes, prevented the ASO from reducing KRAS levels and inhibiting tumor growth in lab models.

The team also discovered a cellular defense that limits the therapy. When endosomes leak near the nucleus, cells form stress granules that plug and repair the membrane. Blocking stress granule formation with the drug ISRIB enhanced the ASO's ability to suppress KRAS production.

Both CD44 and EPHA2 are highly expressed in aggressive pancreatic cancers. CD44 is thought to support tumor growth and therapy-resistant cancer stem cells. The authors propose that this receptor pathway, selected by tumors for their own advantage, could be exploited to deliver therapeutic molecules, and that inhibiting the endosomal repair response may further improve ASO delivery.