title: Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth.
abstract: Gastrointestinal stromal tumor (GIST), originating from the interstitial cells of Cajal (ICC), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib, which targets KIT, most patients with advanced GIST develop resistance and eventually die of the disease. The ETS family transcription factor ETV1 is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that ETV1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target. We further uncover a positive feedback circuit where MAP kinase activation downstream of KIT stabilizes the ETV1 protein, and ETV1 positively regulates KIT expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression in vitro and complete tumor regression in vivo. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management.
  
  
  CONCLUSIONS
  ETV1 is a lineage-specific oncogenic transcription factor required for the growth and survival of GIST. We describe a novel strategy of targeting ETV1 protein stability by the combination of MEK and KIT inhibitors that synergistically suppress tumor growth. This strategy has the potential to change first-line therapy in GIST clinical management.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leili
authors.initials: L
authors.lastname: Ran
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Inna
authors.initials: I
authors.lastname: Sirota
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Devan
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yuedan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shipra
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pharmacology, Weill Cornell Medical College, New York, New York.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kaufmann
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sinan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.affiliation: Division of Human Health and Medical Science, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pharmacology, Weill Cornell Medical College, New York, New York. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York. Cell and Developmental Biology, Weill Cornell Medical College, New York, New York. chip@mskcc.org cheny1@mskcc.org.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York. Cell and Developmental Biology, Weill Cornell Medical College, New York, New York. chip@mskcc.org cheny1@mskcc.org.
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004357:Drug Synergism; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit; D020928:Mitogen-Activated Protein Kinases