Receptor Pathway Lets Antisense Drugs Escape Endosomes to Silence KRAS in Pancreatic Cancer
The discovery points to using CD44 or EPHA2 as delivery targets together with short, controlled inhibition of cellular repair to raise ASO potency.
Overview
- A study published Aug. 11, 2026 in the Journal of Cell Biology found that a KRAS-targeting antisense oligonucleotide (cET‑ASOKRas) binds the cell surface receptor CD44, which activates EPHA2 to anchor ASO-containing endosomes near the nucleus and permit productive escape.
- Perinuclear positioning triggers lipid peroxidation that makes endosomal membranes leaky and allows ASOs to reach cytoplasm and nucleus where they degrade mutant KRAS mRNA.
- Removing CD44 or EPHA2 or blocking EPHA2’s anchoring function dramatically cut ASO uptake and activity, with EPHA2-deficient cells showing more than a 100-fold loss of efficacy.
- Cells limit ASO escape by assembling stress granules that repair damaged endosomes, and pharmacologic inhibition of that response with ISRIB or genetic disruption of stress-granule components increased KRAS silencing in lab models.
- The work used Ionis’s cET‑ASOKRas in mouse and human pancreatic cancer models and is preclinical; next steps include safety tests, optimization of combination strategies to boost endosomal escape, and evaluation of CD44/EPHA2 as biomarkers for targeted delivery.