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K. Takahashi

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-065 - Histone Deacetylase Inhibition Alters Stem Cell Phenotype in Gefitinib-Resistant Lung Cancer Cells with EGFR Mutation (ID 7401)

      09:30 - 16:00  |  Author(s): K. Takahashi

      • Abstract

      Cancer stem cells (CSCs) are epigenetically altered by histone deacetylase (HDAC), resulting in chromatin condensation. We have reported that gefitinib-resistant-persisters (GRP) population within non-small cell lung cancer (NSCLC) cells possesses CSCs features. The purpose of this study is to examine the role of HDAC in the gefitinib-resistant lung CSC.

      We used HDAC1, HDAC2, and HDAC5 as markers of chromatin compaction in GRP of EGFR-mutant NSCLC cells PC9 and HCC827. Gefitinib-resistant tumor (GRT) was established by obtaining the remaining tumor in PC9-injected NOG mice after two weeks of gefitinib treatment. Quantitative real-time PCR were performed to analyze gene expressions. immunofluorescence and fluorescence-immunohistochemistry were performed to analyze protein expressions in the NSCLC cell lines and in vivo biopsy specimens, respectively. HDAC inhibitor Trichostatin-A was used to study the impact on the sensitivity of GRP to gefitinib and the implication on the CSC features.

      PC9-GRP and HCC827-GRP cells expressed high level of HDAC1, HDAC2, and HDAC5. GRT also showed upregulation of HDAC1 compared to naïve PC9 tumor. Inhibition of HDAC reduced CSC-related factors and, reduced sphere formation of GRP, and increased sensitivity to gefitinib. Specimens from lung cancer patients with acquired resistance to gefitinib displayed high expression of HDAC1.

      HDAC is implicated in the CSC phenotype and is involved in the resistance to EGFR-TKI in NSCLC. Inhition of HDAC could be considered to reverse acquired resistance of EGFR-mutant to EGFR-TKI that is mediated by CSC.