Wild-Type H- and N-Ras Promote Mutant K-Ras-Driven Tumorigenesis by Modulating the DNA Damage Response
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, dans des cellules cancéreuses exprimant le gène K-RAS muté, l'expression des gènes non mutés H-Ras et N-Ras est nécessaire pour la tumorigenèse
Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and, consequently, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint and confers specific sensitization of mutant K-Ras cancer cells to DNA damage chemotherapeutic agents in vitro and in vivo. "Mutant K-Ras cancer cells require WT-H/N-Ras for G2 DNA damage checkpoint activation "The activation of ATR/Chk1 in mutant K-Ras cancer cells is dependent on WT-H/N-Ras "WT-H-Ras suppression leads to regression of K-Ras tumors in response to DNA damage Grabocka et al. report that cancer cells expressing mutant K-Ras require wild-type H-Ras and N-Ras to activate the ATR-Chk1-mediated DNA damage checkpoint. This dependence on wild-type H- and N-Ras can be exploited to sensitize K-Ras-driven cancers to DNA damage-inducing chemotherapeutic agents.
Cancer Cell 2014