Cancer Cell
Volume 25, Issue 2, 10 February 2014, Pages 243-256
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Article
Wild-Type H- and N-Ras Promote Mutant K-Ras-Driven Tumorigenesis by Modulating the DNA Damage Response

https://doi.org/10.1016/j.ccr.2014.01.005Get rights and content
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Highlights

  • 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

Summary

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.

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