title: C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression.
abstract: BACKGROUND
  The radiation doses used to treat unresectable lung cancer are often limited by the proximity of normal tissues. Overexpression of c-Met, a receptor tyrosine kinase, occurs in about half of non-small-cell lung cancers (NSCLCs) and has been associated with resistance to radiation therapy and poor patient survival. We hypothesized that inhibiting c-Met would increase the sensitivity of NSCLC cells to radiation, enhancing the therapeutic ratio, which may potentially translate into improved local control.
  
  
  METHODS
  We tested the radiosensitivity of two high-c-Met-expressing NSCLC lines, EBC-1 and H1993, and two low-c-Met-expressing lines, A549 and H460, with and without the small-molecule c-Met inhibitor MK-8033. Proliferation and protein expression were measured with clonogenic survival assays and Western blotting, respectively. γ-H2AX levels were evaluated by immunofluorescence staining.
  
  
  RESULTS
  MK-8033 radiosensitized the high-c-Met-expressing EBC-1 and H1993 cells but not the low-c-Met-expressing cell lines A549 and H460. However, irradiation of A549 and H460 cells increased the expression of c-Met protein at 30 minutes after the irradiation. Subsequent targeting of this up-regulated c-Met by using MK-8033 followed by a second radiation dose reduced the clonogenic survival of both A549 and H460 cells. MK-8033 reduced the levels of radiation-induced phosphorylated (activated) c-Met in A549 cells.
  
  
  CONCLUSIONS
  These results suggest that inhibition of c-Met could be an effective strategy to radiosensitize NSCLC tumors with high basal c-Met expression or tumors that acquired resistance to radiation because of up-regulation of c-Met.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 , USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhardwaj
authors.forename: Yanai
authors.initials: Y
authors.lastname: Zhan
authors.forename: Maria Angelica
authors.initials: MA
authors.lastname: Cortez
authors.forename: Kie Kian
authors.initials: KK
authors.lastname: Ang
authors.forename: David
authors.initials: D
authors.lastname: Molkentine
authors.forename: Anupama
authors.initials: A
authors.lastname: Munshi
authors.forename: Uma
authors.initials: U
authors.lastname: Raju
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: James
authors.initials: J
authors.lastname: Welsh
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002588:Cesium Radioisotopes; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay
chemical_list: D002588:Cesium Radioisotopes; D011838:Radiation-Sensitizing Agents; D019859:Proto-Oncogene Proteins c-met