title: Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response.
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.
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors: Elda
authors: E
authors: Grabocka
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors: Yuliya
authors: Y
authors: Pylayeva-Gupta
authors: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Mathew J K
authors: MJ
authors: Jones
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors: Veronica
authors: V
authors: Lubkov
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors: Eyoel
authors: E
authors: Yemanaberhan
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors: Laura
authors: L
authors: Taylor
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors: Hao Hsuan
authors: HH
authors: Jeng
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: dafna.bar-sagi@nyumc.org.
authors: Dafna
authors: D
authors: Bar-Sagi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins