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J. Feng



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    MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      MA 16.14 - c-Met in Esophageal Squamous Cell Carcinoma: An Independent Prognostic Factor and Potential Therapeutic Target (ID 10539)

      17:10 - 17:15  |  Author(s): J. Feng

      • Abstract
      • Presentation
      • Slides

      Background:
      c-Met is reported to serve as a poor prognostic factor in many malignant tumors. Previous studies have suggested the involvement of c-Met in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients.

      Method:
      The expression of c-Met was immunohistochemically assessed in 180 surgically obtained tissue specimens. The correlation between c-Met expression and patients’ clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with c-Met inhibitor in ESCC cell line.

      Result:
      There was no significantly correlated between c-Met expression and patients’ clinicopathological features. However, there was a significant difference in OS (median: 41.9 vs. 56.7 months; p= 0.001) between the high c-Met and low/negative c-Met expressing groups. In subgroup of patients with adjuvant radiotherapy, high expression of c-Met was correlated with poor disease prognosis (p= 0.002), while there was no significant correlation in patients with adjuvant chemotherapy. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor significantly inhibited the growth of an ESCC cell line with high c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor.

      Conclusion:
      The results of our study identified c-Met expression as an independent prognostic factor in ESCC and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with high c-Met expression.

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    P3.17 - Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies (ID 733)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P3.17-003 - A Selective Small Molecule Inhibitor of C-Met Kinase, BPI-9016M, Has Synergistic Effects with Radiation on Esophageal Squamous Cell Carcinoma (ID 9870)

      09:30 - 09:30  |  Author(s): J. Feng

      • Abstract

      Background:
      c-Met is overexpressed in cancer cells and plays a crucial role in apoptosis evasion. BPI-9016M, a small-molecule inhibitor of c-Met, could enhance the cytotoxicity of various DNA-damaging agents and promote the cell apoptosis. Here, we evaluated the radiosensitizaion potential of BPI-9016M in Eca109 human esophageal squamous cell carcinoma (ESCC) cell line.

      Method:
      Cell viability was determined by CCK8 assay. The radiosensitization effect of BPI-9016M was evaluated by clonogenic survival and progression of tumor xenograft. Cell apoptosis were determined by flow cytometric analysis and TUNAL. Cell apoptosis regulators were detected by western blot analysis. Radiation-induced DNA double strand break (DSB) and homologous recombination repair (HRR) were detected by the activation of ATR-Chk 1/ATM-Chk2 pathways.

      Result:
      BPI-9016M induced radiosensitization in Eca109 cell of ESCC cell line, associated with 1) down-regulating mutation P53 and Bcl-2; 2) decreases phosphorylated ATR and ATM focus formation, and the expression of γ-H2AX; 3) up-regulates the rate of cell apoptosis protein cleaved-Caspase(Figure 1). The combination of BPI-9016M with irradiation delayed the growth of ESCC tumor xenograft to a greater extent compared with either treatment modality alone (P < 0.05). Figure 1. BPI-9016M enhanced radiation induced apoptosis and inhibited ATM- and ATR-dependent DNA damage homologous recombination repair (HRR) pathways analyzed by western blot.

      Conclusion:
      Our findings suggest that the enhanced apoptosis and the inhibition of HRR contribute to radiosensitization by c-Met inhibitor BPI-9016M in ESCC cell.