Scientists in Scotland have discovered how a new cancer drug slips inside pancreatic cancer cells to shut down a faulty protein that makes the disease grow. The finding, published in the Journal of Cell Biology, could help make pancreatic cancer treatments work better — and it all comes down to two tiny doorways on the surface of cancer cells.
Researchers at the Cancer Research UK Scotland Institute and the University of Glasgow studied a drug called cET-ASOKRas, developed by the pharmaceutical company Ionis Pharmaceuticals. The drug belongs to a class of treatments called antisense oligonucleotides, or ASOs — short strands of DNA designed to find and destroy the molecular instructions that tell cancer cells to make harmful proteins. In lab tests, the drug already reduced levels of a faulty protein called KRAS, which drives pancreatic cancer growth.
But scientists did not fully understand how the drug actually gets inside cells to reach its target. The research team, led by postdoctoral researcher Sergi Marco, found that cET-ASOKRas works by first latching onto a receptor — a kind of molecular door — called CD44 on the surface of pancreatic cancer cells. This triggers a second receptor called EPHA2 to pull the drug inside the cell inside tiny bubble-like compartments called endosomes.
Here is the clever part: EPHA2 then positions these endosomes right next to the cell's nucleus, where the drug's target instructions are located. The endosome membranes eventually become leaky, allowing the drug to escape and find its target mRNA — the instruction that tells cells to make the faulty KRAS protein. Once the drug binds to the mRNA, the cell destroys the instruction, stopping production of the harmful protein.
But cancer cells are sneaky. The researchers found that cells respond to leaky endosomes by building protective structures called stress granules that patch up the damage. This limits how well the drug can work. When the scientists used a drug called ISRIB to block stress granule formation, the cET-ASOKRas treatment became much more effective at shutting down KRAS production.
Both CD44 and EPHA2 are present at high levels in aggressive pancreatic cancers, making this pathway a promising target for treatment. Professor Jim C. Norman said the team believes this receptor pathway, which tumors use to support their growth, could be exploited to deliver therapeutic molecules directly to resistant cancers. Norman added that drugs targeting the cell's stress response could further boost how well these treatments work.
Pancreatic cancer is one of the most difficult cancers to treat, and new approaches are urgently needed. This discovery gives scientists a clearer roadmap for how to deliver cancer-fighting drugs more effectively — and how to overcome the tricks cancer cells use to resist treatment.