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Fariz Nurwidya



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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  |  Presenting Author(s): Fariz Nurwidya

      • Abstract

      Background:
      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.

      Method:
      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.

      Result:
      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.

      Conclusion:
      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.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-024 - Role of FBXW7 in the Maintenance of Quiescent Cancer Stem Cells Resistant to Gefitinib in EGFR Mutation-Positive Non-Small Cell Lung Cancer (ID 8160)

      09:30 - 16:00  |  Author(s): Fariz Nurwidya

      • Abstract

      Background:
      Accumulating evidence indicates that quiescent cancer stem cells (CSCs) are involved in the resistance to gefitinib in non-small cell lung cancer (NSCLC) as non-mutational mechanism. We have previously reported that gefitinib-resistant persisters (GRPs) highly expressed stemness factors and had characteristic features of the CSCs phenotype. Recent studies demonstrate that FBXW7, a type of F-box protein, plays an important role in the maintenance of quiescent CSC by mediating the degradation of c-Myc protein by ubiquination. The aim of this study is to figure out the role of FBXW7 in the resistance to gefitinib in NSCLC with EGFR mutation.

      Method:
      NSCLC cell lines, PC9 and HCC827, harboring sensitive-EGFR mutation were exposed to high concentration of gefitinib in order to develop GRPs. We tried to knockdown FBXW7 gene expression, and evaluated their sensitivity to gefitinib and CD133-positive stem cell population in GRPs. We also introduced FUCCI plasmid via lentiviral infection in the cells and then investigated the cell cycle and G0-phase cells in GRPs. Furthermore, we established gefitinib-resistant tumor (GRT) model by injecting PC9 cells into NOG-mice followed by gefitinib administration after tumor growth, and evaluated mRNA and protein expression of quiescence-related markers including FBXW7 in vivo.

      Result:
      In vitro, GRPs showed high expression of stem cell marker CD133 and quiescence-related markers including FBXW7 and low expression of c-Myc at protein level. Cell cycle analysis revealed that majority of GRPs existed in G0/G1 phase. Silencing of FBXW7 gene reduced CD133-positive cell population in GRPs. Knockdown of FBXW7 also increased susceptibility of cells to gefitinib, reversed population of G0/G1-arrest cells to G2/S/M cells, and decreased cell number of GRPs. In vivo, GRTs after gefitinib treatment revealed high expression of FBXW7 and low expression of c-Myc.

      Conclusion:
      These findings suggest that FBXW7 may play a pivotal role in the maintenance of quiescent CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.