- Antisense oligonucleotides (ASOs) have shown promise in cancer therapy but face challenges in entering cells and escaping endosomes.
- A new study identifies that ASOs bind to CD44, activating EPHA2, which directs endosomes to accumulate near the nucleus.
- Endosomal membranes become leaky, allowing ASOs to escape and suppress KRAS expression.
- Cells form stress granules to repair leaks, which limits ASO activity; blocking this with ISRIB enhances efficacy.
- Findings published in the Journal of Cell Biology suggest new delivery strategies for ASOs.
- ASOs have transformed treatment for several rare genetic diseases, but progress in cancer has been slower due to molecules becoming trapped inside endosomes.
- The study focused on cET-ASO^KRas, an antisense drug developed by Ionis Pharmaceuticals to target mutant KRAS mRNAs.
- CD44 and EPHA2 are highly expressed in aggressive pancreatic cancers, potentially providing a natural entry route for therapeutic molecules.
Researchers from the Cancer Research UK Scotland Institute and the University of Glasgow have uncovered a novel pathway involving CD44 and EPHA2 that enhances the delivery of antisense oligonucleotides (ASOs) into pancreatic cancer cells.18
This pathway is crucial for silencing the mutant KRAS gene, which drives tumor growth in pancreatic cancer.
The study, published in the Journal of Cell Biology, reveals that the uptake of a specific ASO targeting mutant KRAS begins when it binds to the cell-surface receptor CD44. This interaction activates EPHA2, which directs ASO-containing endosomes to accumulate near the nucleus, facilitating their escape into the cytoplasm where they can effectively bind to their target mRNA.
The researchers demonstrated that deleting either CD44 or EPHA2 significantly reduced ASO uptake and KRAS suppression, with the ASO being over 100-fold less effective in cells lacking EPHA2.
Additionally, the study identified a cellular mechanism that limits ASO activity. When endosomal membranes become damaged, cells form stress granules that help repair leaks, reducing ASO escape. Treatment with ISRIB, an inhibitor of stress granule formation, significantly enhanced KRAS silencing.34
The findings suggest that the CD44-EPHA2 pathway could be exploited to improve ASO delivery in aggressive pancreatic tumors, potentially leading to more effective therapies against this challenging cancer type.
The work does not yet establish an effective treatment for patients, but it identifies a series of molecular checkpoints that could guide the design of more efficient antisense therapies.
“The pathway relies on CD44 binding to activate EPHA2, which anchors endosomes near the nucleus; deleting either receptor made the ASO over 100-fold less effective. Blocking stress granule formation with ISRIB enhanced KRAS suppression, suggesting combination strategies for next-generation therapies.”
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