Early elevations of RAS protein level and activity are critical for the development of PDAC in the context of...

The KRAS^G12D mutation was believed to be locked in a GTP-bound form, rendering it fully active. However, recent studies have indicated that the presence of mutant KRAS alone is insufficient; it requires additional activation through inflammatory stimuli to effectively drive the development of pancreatic ductal adenocarcinoma (PDAC). It remains unclear to what extent RAS activation occurs during the development of PDAC in the context of inflammation. Here, in a mouse model with the concurrent expression of Kras^G12D/+ and inflammation mediator IKK2 in pancreatic acinar cells, we showed that, compared to KRAS^G12D alone, the cooperative interaction between KRAS^G12D and IKK2 rapidly elevated both the protein level and activity of KRAS^G12D and NRAS in a short term. This high level was sustained throughout the rest phase of PDAC development. These results suggest that inflammation not only rapidly augments the activity but also the protein abundance, leading to an enhanced total amount of GTP-bound RAS (KRAS^G12D and NRAS) in the early stage. Notably, while KRAS^G12D could be further activated by IKK2, not all KRAS^G12D proteins were in the GTP-bound state. Overall, our findings suggest that although KRAS^G12D is not fully active in the context of inflammation, concurrent increases in both the protein level and activity of KRAS^G12D as well as NRAS at the early stage by inflammation contribute to the rise in total GTP-bound RAS.