title: Targeting epithelial-to-mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer.
abstract: OBJECTIVE
  Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met-mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models.
  
  
  METHODS
  SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N = 87) and relapse (N = 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome.
  
  
  RESULTS
  We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease.
  
  
  CONCLUSIONS
  These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease.
authors.affiliation: Authors' Affiliations: Cancer Research Program, Epithelial to Mesenchymal Transition Laboratory, Cancer Research Program, IMIM; Consulting Service on Methodology for Biomedical Research; Departments of Oncology and Pathology, Hospital del Mar; Universitat Pompeu Fabra, Barcelona; Departments of Pathology and Oncology, IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: Cañadas
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Taus
authors.forename: Oriol
authors.initials: O
authors.lastname: Arpí
authors.forename: Montserrat
authors.initials: M
authors.lastname: Arumí-Uría
authors.forename: Lara
authors.initials: L
authors.lastname: Pijuan
authors.forename: Silvia
authors.initials: S
authors.lastname: Menéndez
authors.forename: Sandra
authors.initials: S
authors.lastname: Zazo
authors.forename: Manuel
authors.initials: M
authors.lastname: Dómine
authors.forename: Marta
authors.initials: M
authors.lastname: Salido
authors.forename: Sergi
authors.initials: S
authors.lastname: Mojal
authors.forename: Antonio
authors.initials: A
authors.lastname: García de Herreros
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.forename: Edurne
authors.initials: E
authors.lastname: Arriola
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C066855:HGF protein, human; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; D005047:Etoposide; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met