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.

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