Author of

• 20194

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  P3.15 - SCLC/Neuroendocrine Tumors (ID 731)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: SCLC/Neuroendocrine Tumors
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24208

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    P3.15-001 - The Impact of MET Inhibition on Small-Cell Lung Cancer Cells Exhibiting Aberrant Activation of the HGF/MET Pathway (ID 7898)

    09:30 - 09:30  |  Author(s): S. Sakamoto
    • Abstract

    Background:
    Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as being extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF). Although aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion, the mechanisms in SCLC have not been elucidated clearly. The aim of the present study was to evaluate the effect of inhibiting the HGF/MET pathway on tumor progression in SCLC with multi-organ metastasis.
    
    Method:
    We used eight human SCLC cell lines to elucidate the effect of MET inhibition on tumor progression. MET inhibitors, crizotinib and golvatinib, were used in this study in vitro and in vivo.
    
    Result:
    We found that the HGF/MET signaling was aberrantly activated in chemo-resistant or chemo-relapsed SCLC cell lines (SBC-5, DMS273, and DMS273-G3H) by the secretion of HGF and/or MET copy number gain. HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA-mediated knockdown of HGF or MET, constrained growth of these SCLC cells via the inhibition of ERK and AKT signals. We also revealed that treatment with either crizotinib or golvatinib in vivo suppressed the systemic metastasis of SBC-5 cell tumors in NK cell-depleted SCID mice, predominantly via cell cycle arrest.
    
    Conclusion:
    These findings reveal that the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells exhibiting aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET-mediated signaling in SCLC cells.