A novel KRAS-AGO2 interaction in cancer
Nearly a third of all cancers have mutations in the RAS family of genes, including KRAS; however therapeutic targeting of RAS family has remained elusive. MCTP researchers uncovered an interaction between KRAS and Argonaute 2 (AGO2) and found that AGO2 interacted with both mutated and normal KRAS.
Endogenously, KRAS and AGO2 co-sedimented and co-localized in the
endoplasmic reticulum. Functionally, AGO2 knockdown attenuates cell proliferation in mutant KRAS-dependent cells and AGO2 overexpression enhances KRASG12V-mediated transformation. Using AGO2−/−
cells, they demonstrated that the KRAS-AGO2 interaction is required for
maximal mutant KRAS expression and cellular transformation.
Mechanistically, oncogenic KRAS attenuates AGO2-mediated gene silencing.
Overall, the functional interaction with AGO2 extends KRAS function
beyond its canonical role in signaling. These findings suggest interrupting the KRAS-AGO2 interaction as a potential therapeutic strategy.