Interactions of Cancer-causing Gene May Lead to Therapeutic Target
An exploration of the interaction between the protein produced by the common cancer-causing KRAS gene and the AGO2 protein may lead to the possibility of interrupting the KRAS-AGO2 interaction as a possible therapy. This study, done in cancer cell lines and mice, was published in Cell Reports.1
KRAS is one of the most common cancer-causing genes, and it has been thought to be undruggable. This study addressed the puzzle of KRAS by examining its interactions.
"We came at this from a different angle," says Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology in Ann Arbor, and author of the study. "Knowing how critical KRAS is in cancer development, we looked for important protein interactions that we might try to disrupt. We picked up on an interactor called AGO2. It was a very robust interaction."
Mutations in the RAS family of genes, including KRAS, occur in almost one-third of all cancers. KRAS mutations drive nearly all pancreatic tumors, which is a particularly aggressive and difficult-to-treat disease.
AGO2 impacts many genes through its roles in silencing genes and processing microRNA. The researchers, from the University of Michigan Comprehensive Cancer Center, found that AGO2 interacted with both mutated and normal KRAS, and this link occurred in all 12 cell lines tested.
Using cancer cell lines and mouse models, this study showed that AGO2 enhanced the cancer-causing ability of KRAS. When AGO2 levels were higher, so was cancerous activity. Also, AGO2's ability to process microRNA was inhibited by KRAS. This affected downstream oncogenes and tumor suppressor genes that are controlled by microRNA.
A likely next step from this research is to explore interrupting KRAS-AGO2 interactions, which could lead to a possible therapy. The study authors' next plan is to attempt to reproduce their cell findings in a mouse model and to map their findings in 3D to identify potential therapy opportunities.
"This is not a near-term solution. It is a basic science discovery that has potential to be translated. It's exciting to consider that KRAS may not be the undruggable target we thought it is," Chinnaiyan said.
1. Shankar S, Pitchiaya S, Malik R, et al. KRAS engages AGO2 to enhance cellular transformation. Cell Rep. 2016;14(6):1448-1461.