title: Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation.
abstract: Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2-M cell-cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1-S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1-S and G2-M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wild-type p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell-cycle distribution profiling indicates constantly lower G1 and higher G2-M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared with the parental counterpart.
  
  
  CONCLUSIONS
  The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, as p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA-damaging agents for MET-positive/p53-negative tumors.
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: K
authors.initials: K
authors.lastname: Mikami
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: M
authors.initials: M
authors.lastname: Medová
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: L
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: P
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: A A
authors.initials: AA
authors.lastname: Glück
authors.affiliation: Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: M P
authors.initials: MP
authors.lastname: Tschan
authors.affiliation: Merck Serono Research & Development, Merck KGaA, Darmstadt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Blaukat
authors.affiliation: Merck Serono Research & Development, Merck KGaA, Darmstadt, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Bladt
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: D M
authors.initials: DM
authors.lastname: Aebersold
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. yitzhak.zimmer@insel.ch.
authors.forename: Y
authors.initials: Y
authors.lastname: Zimmer
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: C582858:EMD1214063; D011724:Pyridazines; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met