Author of

• 12418

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  P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12428

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    P3.05-011 - Targeting epithelial to mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer (ID 2082)

    09:30 - 09:30  |  Author(s): O. Arpí
    • Abstract

    Background
    Met receptor phosphorylation is associated with poor prognosis in human SCLC. Several Met inhibitors are being tested for the treatment of different neoplasms. Met activation has been shown to be an inductor of epithelial to mesenchymal transition (EMT) in a number of tumor models. The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met induced EMT in SCLC, to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models and to investigate the significance of EMT in human SCLC.

    Methods
    Biological features (growth, invasiveness, tumorogenesis) and chemosensitivity of SCLC models (H69) of HGF-induced EMT (H69M) were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice). Mice with mesenchymal chemoresistant SCLC xenografts were treated with etoposide, the Met inhibitor PF-2341066 (Crizotinib) and the combination. Human SCLC samples at diagnosis and relapse were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and correlated these with patient outcome. Association between clinical-pathological characteristics were tested with Chi-Square and Fisher tests. Differences in survival according to biomarker status were evaluated by log-rank and Cox regression models, assuming a 2-sided statistical significance p< 0.05.

    Results
    We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers (Snail1, SPARC, vimentin) and downregulation of E-cadherin. This derived in increased tumorogenesis, local invasion and chemoresistance in xenograft models. The combination of etoposide and PF-2341066, but not the Met inhibitor alone significantly decreased tumor growth in this chemoresistant/mesenchymal models. Moreover, Snail1, SPARC and vimentin expression in human SCLC specimens (N:87) was significantly associated with Met activation (co-localization by immunofluorescence). Expression of mesenchymal markers predicted worse survival (all p-values <0.05) in the multivariate analysis. In 5 paired biopsies, we observed upregulation of mesenchymal markers and p-Met in chemorefractory disease.

    Conclusion
    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.