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K. Fukuda

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    MINI 09 - Drug Resistance (ID 107)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI09.12 - HDAC Inhibitors Overcome New Generation EGFR-TKI-Resistance Caused by Homozygous BIM Polymorphism in EGFR Mutant Lung Cancer (ID 885)

      16:45 - 18:15  |  Author(s): K. Fukuda

      • Abstract
      • Slides

      The BIM deletion polymorphism in intron 2 was found in a significant percent (~13%) of the Asian population, with 0.5% of individuals being homozygous for this deletion. Patients with EGFR mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to 1[st] generation EGFR-TKIs, gefitinib and erlotinib. We recently reported that the histone deacetylase (HDAC) inhibitor vorinostat can epigenetically restore BIM function and death sensitivity of EGFR-TKI, in cases of EGFR mutant lung cancer where resistance to 1[st] generation EGFR-TKI is associated with a heterozygous BIM polymorphism. Here, we examined 1) whether BIM polymorphism associated with resistance to new generation EGFR-TKIs and 2) whether vorinostat could overcome EGFR-TKI resistance in EGFR mutant lung cancer cells with a homozygous BIM polymorphism.

      We used EGFR mutant lung cancer cells lines, PC-9, PC-9[i2BIM-/-] (a genetically engineered subclone that was homozygous for BIM deletion polymorphism), and PC-3 (heterozygous for BIM deletion polymorphism). These cell lines were treated with gefitinib, afatinib (2[nd] generation), and AZD9291 (3[rd] generation). Apoptosis was evaluated by FACS and expression of cleaved-caspase 3/7 and PARP by western blot.

      While PC-9 cells were sensitive to all EGFR-TKIs in terms of apoptosis induction, both of PC-3 and PC-9[i2BIM-/- ] cells were resistant to 1[st] generation EGFR-TKIs and new generation EGFR-TKIs as well. Vorinostat combined with new generation EGFR-TKIs induced apoptosis of PC-3 and PC-9[i2BIM-/- ] cells in vitro. In the subcutaneous tumor model, AZD9291 regressed the tumors produced PC-9 cells but not PC-9[i2BIM-/- ] cells, indicating in vivo resistance of PC-9[i2BIM-/- ] cells to EGFR-TKIs. Combined use of vorinostat with AZD9291 successfully decreased the size of tumors produced by PC-9[i2BIM-/-] cells by inducing tumor cell apoptosis.

      These observations indicated that BIM deletion polymorphism is associated with apoptosis resistance caused not only by 1[st] generation EGFR-TKIs but also by new generation EGFR-TKIs. Moreover, combined use of HDAC inhibitor may overcome EGFR-TKI resistance associated not only with heterozygous deletion but also with homozygous deletion in the BIM gene.

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