title: Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer.
abstract: OBJECTIVE
  Deregulated signaling via the MET receptor tyrosine kinase is abundant in gastric tumors, with up to 80% of cases displaying aberrant MET expression. A growing body of evidence suggests MET as a potential target for tumor radiosensitization.
  
  
  METHODS
  Cellular proliferation and DNA damage-induced senescence were studied in a panel of MET-overexpressing human gastric cancer cell lines as well as in xenograft models after MET inhibition and/or ionizing radiation. Pathways activation and protein expression were assessed by immunoblotting and immunohistochemistry. Tumor tissue microarrays (91 gastric cancer patients) were generated and copy number alteration (178 patients) and gene expression (373 patients) data available at The Cancer Genome Atlas were analyzed to assess the coalterations of MET and FOXM1.
  
  
  RESULTS
  MET targeting administered before ionizing radiation instigates DNA damage-induced senescence (∼80%, P < 0.001) rather than cell death. MET inhibition-associated senescence is linked to the blockade of MAPK pathway, correlates with downregulation of FOXM1, and can be abrogated (11.8% vs. 95.3%, P < 0.001) by ectopic expression of FOXM1 in the corresponding gastric tumor cells. Cells with ectopic FOXM1 expression demonstrate considerable (∼20%, P < 0.001) growth advantage despite MET targeting, suggesting a novel clinically relevant resistance mechanism to MET inhibition as the copresence of both MET and FOXM1 protein (33%) and mRNA (30%) overexpression as well as gene amplification (24,7%) are common in patients with gastric cancer.
  
  
  CONCLUSIONS
  FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. Clin Cancer Res; 22(21); 5322-36. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Francica
authors.affiliation: Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Lluís
authors.initials: L
authors.lastname: Nisa
authors.affiliation: Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Aebersold
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Merck Serono Research & Development, Merck KGaA, Darmstadt, Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Bladt
authors.affiliation: Merck Serono Research & Development, Merck KGaA, Darmstadt, Germany.
authors.forename: Andree
authors.initials: A
authors.lastname: Blaukat
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.|Department of Visceral Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stroka
authors.affiliation: IBM Research, Zurich Research Laboratory, Zurich, Switzerland.
authors.forename: María Rodríguez
authors.initials: MR
authors.lastname: Martínez
authors.affiliation: Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Zimmer
authors.affiliation: Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. michaela.medova@dkf.unibe.ch.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Medová
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000072278:Forkhead Box Protein M1 / Q000235:genetics*; D005784:Gene Amplification / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D047428:Protein Kinase Inhibitors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met