title: c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma.
abstract: BACKGROUND
  Activation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and inhibition in a large cohort of RCC tumors and cell lines.
  
  
  METHODS
  c-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines.
  
  
  RESULTS
  Higher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% confidence interval (CI) 1.08-1.74; P = 0.0091] and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197.
  
  
  CONCLUSIONS
  c-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.
authors.affiliation: Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa. Electronic address: geoffrey.gibney@moffitt.org.
authors.forename: G T
authors.initials: GT
authors.lastname: Gibney
authors.affiliation: Section of Medical Oncology, Yale Cancer Center.
authors.forename: S A
authors.initials: SA
authors.lastname: Aziz
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven.
authors.forename: R L
authors.initials: RL
authors.lastname: Camp
authors.affiliation: Section of Medical Oncology, Yale Cancer Center.
authors.forename: P
authors.initials: P
authors.lastname: Conrad
authors.affiliation: Clinical Development, ArQule, Inc., Woburn.
authors.forename: B E
authors.initials: BE
authors.lastname: Schwartz
authors.affiliation: Clinical Development, ArQule, Inc., Woburn.
authors.forename: C R
authors.initials: CR
authors.lastname: Chen
authors.affiliation: Departments of Medical Oncology and Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Kelly
authors.affiliation: Section of Medical Oncology, Yale Cancer Center.
authors.forename: H M
authors.initials: HM
authors.lastname: Kluger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology; D046888:Tissue Array Analysis
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); C551661:ARQ 197; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D010879:Piperazines; D011760:Pyrrolidinones; D011804:Quinolines; D013449:Sulfonamides; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met