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Cancer Cell. 2014 Feb 10;25(2):243-56. doi: 10.1016/j.ccr.2014.01.005.

Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response.

Author information

1
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
2
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: dafna.bar-sagi@nyumc.org.

Abstract

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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PMID:
24525237
PMCID:
PMC4063560
DOI:
10.1016/j.ccr.2014.01.005
[Indexed for MEDLINE]
Free PMC Article

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