Author of

• 16549

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  P1.02 - Poster Session with Presenters Present (ID 454)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 16596

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    P1.02-047 - Effect of Dasatinib on EMT-Mediated-Mechanism of Resistance against EGFR Inhibitors in Lung Cancer Cells (ID 5809)

    14:30 - 14:30  |  Author(s): T. Takemoto
    • Abstract

    Background:
    The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells. In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells harboring EGFR exon 19 deletion, which tend to acquire resistance to EGFR-TKIs via EMT in previous reports.The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells. In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells harboring EGFR exon 19 deletion, which tend to acquire resistance to EGFR-TKIs via EMT in previous reports.
    
    Methods:
    HCC4006ER cells with an EMT phenotype were previously established by chronic exposure to increasing concentrations of erlotinib. Sensitivity to dasatinib in parental HCC4006 and HCC4006ER cells was analyzed. Subsequently, HCC4006EDR cells were established by chronic treatment with combination of erlotinib and dasatinib. The expression of EMT markers of these cells and the mechanism of acquired resistance to this combination therapy were analyzed.
    
    Results:
    Short-term or long-term, ranging OOhours to XXXmonth, treatment with dasatinib did not reverse EMT in HCC4006ER. In contrast, HCC4006EDR cells maintained an epithelial phenotype, and the mechanism underlying resistance to erlotinib plus dasatinib combination therapy was attributable to a T790M secondary mutation. HCC4006EDR cells, but not HCC4006ER cells, were highly sensitive to a third-generation EGFR-TKI, osimertinib.
    
    Conclusion:
    Although dasatinib monotherapy did not reverse EMT in HCC4006ER cells, preemptive combination treatment with erlotinib and dasatinib prevented the emergence of acquired resistance via EMT, and led to the emergence of T790M. Our results indicate that preemptive combination therapy may be a promising strategy to prevent the emergence of EMT-mediated resistance.