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I. Kinoshita



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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-014 - Effects of combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor and the histone deacetylase inhibitor on NSCLC cells. (ID 2680)

      12:32 - 12:46  |  Author(s): I. Kinoshita

      • Abstract

      Background
      EZH2, a polycomb group protein, has histone methyltransferase activity, and is involved in malignant transformation of several cancers. We have previously shown that an EZH2 inhibitor, DZNep, inhibits growth of non-small cell lung cancer (NSCLC) cell lines via G1 arrest and apoptosis. Recent studies have shown that EZH2-mediated gene silencing requires a recruitment of the histone deacetylase (HDAC) activity. Co-treatment with DZNep and an HDAC inhibitor has been shown to induce apoptosis synergistically in AML, ovarian cancers and renal cancers. However, the effect of combined therapy with DZNep and an HDAC inhibitor on NSCLC cells has not been reported.

      Methods
      We evaluated the effect of combined therapy with DZNep and an HDAC inhibitor, SAHA, on four human NSCLC cell lines, H1299, H1975, A549 and PC-3. Cell proliferation of untreated or drug-treated cells was measured by MTT assay. Percentage of apoptotic cells was measured using FITC-conjugated annexin V with a flow cytometer. Western blot analysis was performed on total cell lysates.

      Results
      Co-treatment with DZNep and SAHA inhibited cell proliferation synergistically, and reduced EZH2 expression and histone H3 lysine 27 trimethylation more effectively compared with each agent alone. The co-treatment greatly induced accumulation of p27[ Kip1] and decrease in cyclin A expression. Flow cytometry analysis demonstrated that the apoptotic fraction was increased in an additive or synergistic manner by the combination therapy. These effects were more evident in H1975 and PC-3 cells with EGFR mutation, in which expression of EGFR and phosphorylation of EGFR, AKT and ERK1/2 were markedly decreased by the co-treatment.

      Conclusion
      Combined epigenetic therapy with an EZH2 inhibitor and an HDAC inhibitor may represent an effective strategy for NSCLCs.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-010 - Expression of α1,6-fucosyltransferase is associated with prognosis and histology in non-small cell lung cancers (ID 1144)

      09:30 - 09:30  |  Author(s): I. Kinoshita

      • Abstract

      Background
      Lung cancer is one of the leading causes of cancer death throughout the world. A more sophisticated understanding of the pathogenesis and biology of NSCLCs could provide useful information for predicting clinical outcome and personalized treatment. α1,6-FT is the only one enzyme responsible for the core α1,6-fucosylation of N-glycans of glycoproteins, including EGF receptor, TGF-β1 receptor, and integrin α3β1.

      Methods
      α1,6-FT expression was studied by immunohistochemistry in a cohort of 129 surgically resected NSCLCs, classified categorically based on the proportion of positively stained cancer cells (high, > 20%; or low, < 20%), and analyzed statistically in relation to various characteristics, including histology, survival and prognosis.

      Results
      High and low expression of α1,6-FT was found in 67 and 62 of 129 NSCLCs, respectively. Multivariate logistic regression analysis revealed a significant association between high α1,6-FT expression and non-squamous cell carcinoma (mostly adenocarcinoma), as compared with squamous cell carcinomas (odds ratio, 3.51; p = 0.008). Patients with tumors having high α1,6-FT expression had significantly shorter survival time than patients with tumors having low expression in potentially curatively resected NSCLCs (p = 0.03) and adenocarcinomas (p = 0.009), as well as in pStage I NSCLCs (p = 0.03) by the log-rank test. Surprisingly, in pStage I adenocarcinomas, none of 15 patients with tumors having low expression died of lung cancer, although 12 of 23 patients with tumors having high α1,6-FT expression died of lung cancer. High α1,6-FT expression was a significant and independent unfavorable prognostic factor in potentially curatively resected NSCLCs (hazard ratio, 1.81; p = 0.047) and in pStage I NSCLCs (hazard ratio 2.55; p = 0.03) by Cox’s proportional hazards model analysis.

      Conclusion
      These results suggest that α1,6-FT may play a pivotal role for the biological characteristics of NSCLCs. α1,6-FT expression is associated with histology of NSCLCs, and may be a new prognostic marker for overall NSCLCs and adenocarcinomas.