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A.Y. Chang



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    O27 - Clinical Trials and Practice (ID 142)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Other Topics
    • Presentations: 1
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      O27.08 - DISCUSSANT (ID 4015)

      16:15 - 17:45  |  Author(s): A.Y. Chang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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
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      P3.05-012 - Potential Biomarkers of Growth Inhibition of Afatinib (BIBW-2992) in Combination with Dasatinib (BMS-354825) in Gefitinib Resistant Non Small Cell Lung Cancer Cells (NSCLC) (ID 2108)

      09:30 - 16:30  |  Author(s): A.Y. Chang

      • Abstract

      Background
      Gefitinib or Erlotinib (EGFR-TKI) is the first choice of treatment for advanced NSCLC patients harbouring activating EGFR mutations. In addition to primary resistance, acquired resistance to EGFR-TKI eventually occurred in patients after an initial response. New agents have been developed to specifically inhibit the signaling pathways involved in mediating resistance. Because of heterogeneous resistant mechanisms, single agent usually had limited efficacy. Thus drug combination therapy may offer more benefits by synergistic interactions and avoidance of resistance emergence. We studied the combination of afatinib (an irreversible ErbB family inhibitor) and dasatinib (an inhibition of Src, BCR-ABL, PDGFR, Eph) in 8 different genetically characterized NSCLC cell lines to evaluate resistance mechanisms and molecular predicting biomarkers.

      Methods
      Growth inhibition was assessed by MTS assay. The interaction between two different drugs was evaluated by the method of Chou and Talalay. EGFR and k-Ras mutations were tested by direct DNA sequencing. EGFR, HER2, Src and downstream proteins FAK, Akt, MAPK42/44, Stat3, Stat5 expressions were measured by western blot.

      Results
      The efficacy of dasatinib against NSCLC cells in vitro is significantly more potent than gefitinib (p<0.001) and anti-EGFR monoclonal antibody cetuximab (p<0.05). Afatinib demonstrated increased activity against gefitinib and cetuximab resistance cell lines. Synergistic interaction (combination index, CI< 1) between dasatinib and afatinib was found in 7 NSCLC cell lines except A549. The efficacy of dasatinib in combination with afatinib is significantly stronger than that of cetuximab in combination with afatinib (p<0.001). In gefitinib resistant cell lines, growth inhibition by dasatinib was correlated with the ratio of p-Akt/t-Akt (p<0.05); total FAK expression is correlated to the growth inhibition by afatinib (p<0.05); CI results between dasatinib and afatinib were correlated with the active ratio of p-FAK925/t-FAK (p<0.05). In H1650 cell line, which was resistant to both dasatinib and afatinib, the combination of both drugs significantly inhibited the activity of p-EGFR845, p-FAK925, p-Src416, p-Akt473 and p-MAPK42/44 when comparing with that treated by afatinib or dasatinib alone (p<0.05). No significant inhibition was found on p-Stat3 and p-Stat5 by dasatinib. Afatinib was able to reduce the activity of Stat3 but not Stat5. No significant effect was shown on p-Stat3 and p-Stat5 by the combination of afatinib and dasatinib.

      Conclusion
      Our study showed synergistic combination of afatinib and dasatinib is more potent than cetuximab plus afatinib against gefitinib resistant NSCLC cells; it inhibited cell proliferation in H1650 cell line via affecting SFK/FAK, PI3K/PTEN/Akt, and Ras/Raf/MEK/ERK, but not JAK/Stat pathways. The level of p-FAK925/t-FAK may be a useful biomarker predicating synergism between afatinib and dasatinib for the treatment of gefitinib resistant NSCLC cells. P-Akt/t-Akt and total FAK expression may be related to sensitivity to dasatinib and afatinib respectively.