Nearly a third of all cancers have mutations in the RAS family of genes, including KRAS. In pancreatic cancer, a particularly aggressive and difficult-to-treat disease, almost every tumor is driven by KRAS mutations. But KRAS has been thought to be "undruggable" - researchers cannot identify an effective therapy against it.
Researchers exposed a key interaction with AGO2 that may contribute to why mutations in KRAS lead to cancer. AGO2 plays a role in silencing genes and processing microRNA - so it impacts many genes. The researchers found AGO2 interacted with both mutated and normal KRAS. The link appeared in all 12 of the cell lines tested. The study appears in Cell Reports.
Studies in cell lines and mouse models showed that AGO2 enhanced the cancer-causing ability of KRAS. The higher the level of AGO2, the more cancerous activity, the researchers found. At the same time, KRAS inhibits AGO2's ability to process microRNA. This impacts the downstream oncogenes and tumor suppressor genes controlled by microRNA.
The finding suggests potential to explore interrupting the KRAS-AGO2 interaction as a possible therapy. Additional research is needed. The study authors plan next to try to replicate their cell findings in a mouse model to confirm the interaction. They will also begin to map it in 3D to begin to identify opportunities for potential therapies.