E. Shyam P. Reddy, Professor and Director of the Cancer Biology Program at Morehouse School of Medicine, shared on LinkedIn:
“Antisense oligonucleotides (ASOs) can selectively switch off disease-causing genes, making them a promising therapeutic strategy for cancer and other disorders.
But despite years of development, their success in oncology has been limited by a fundamental challenge: scientists have not fully understood how these short strands of DNA enter cells, escape intracellular compartments, and reach their RNA targets.
A new study published in the Journal of Cell Biology identifies a previously unknown trafficking pathway that could help overcome this barrier.
Researchers from the Cancer Research UK Scotland Institute, the University of Glasgow, and collaborators at Ionis Pharmaceuticals found that a KRAS-targeting ASO follows a specific route into pancreatic cancer cells that is essential for silencing the cancer-driving gene.
Although ASOs have transformed treatment for several rare genetic diseases, progress in cancer has been slower because most molecules become trapped inside membrane-bound endosomes after entering tumor cells.
Only a small fraction escapes into the cytoplasm or nucleus, where ASOs bind messenger RNA (mRNA) and trigger its degradation. Improving intracellular delivery is widely considered one of the biggest challenges in advancing ASO therapies for cancer.
Using a constrained ethyl ASO targeting mutant KRAS, the team discovered that productive uptake begins when the ASO binds directly to the cell-surface receptor CD44.
This interaction activates signaling that phosphorylates a second receptor, EPHA2, which then directs ASO-containing endosomes to accumulate near the nucleus.
Once positioned near the nucleus, the endosomal membranes undergo lipid peroxidation, making them leaky and allowing the ASOs to escape into the cell, where they can bind their target mRNA and suppress KRAS expression.”