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J. Edwards



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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.08 - NF-kB in cisplatin resistance and as a prognostic marker in Malignant pleural mesothelioma (ID 3338)

      16:55 - 17:00  |  Author(s): J. Edwards

      • Abstract
      • Presentation
      • Slides

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Currently rates of MPM are rising and estimates indicate that the incidence of MPM will peak in western world within the next 10-15 years. Untreated, MPM has a median survival time of 6 months, with poor survival rates for most patients after 24 months of diagnosis. Nuclear Factor kappa B (NF-kB) is a pro-inflammatory transcription factor which is activated in many cancer types, including MPM. The NF-kB pathway regulates important cellular processes including survival and proliferation signals, which are often found to be dysregulated in cancer. Furthermore, we and others have shown that increased NF-kB activation is linked to development of cisplatin resistance. We aim to outline the potential role of NF-kB as a mediator of cisplatin resistance in MPM and determine its value as a potential candidate for therapeutic intervention.

      Methods
      NF-kB expression was examined in a cohort of MPM patients (n=200) by IHC, and correlated with clinicopathological variables and survival. NF-kB expression was examined in both a panel of MPM cell lines and isogenic parent/cisplatin resistant cell lines by Western blot analysis. The effect of NF-kB inhibition on cellular proliferation was measured by BrdU assay, in a panel of MPM and isogenic parent/cisplatin resistant cell lines, using the novel NF-kB inhibitor Dehydroxymethylepoxyquinomicin (DHMEQ). In addition, the effect of DHMEQ on nuclear translocation of NF-kB was examined by high content screening (HCS).

      Results
      Cytoplasmic or membranous immunostaining was seen in the majority of tumour samples (96.5%), but nuclear localisation of NF-kB was seen in only 11% cases. Kaplan-Meier survival analysis showed that nuclear NF-kB expression correlated with reduced survival (p=0.05). There was no significant correlation between the level of expression of NF-kB and standard clinicopathological parameters. NF-kB was expressed in all MPM cell lines tested to a varying extent (n=20), with no associations to histology. NF-kB levels were shown to be elevated in cisplatin resistant cell lines when compared to the isogenic parent from which they were derived. DHMEQ was shown to reduce nuclear translocation of NF-kB, inhibiting cell proliferation in all cell lines but to a lesser extent in NCI 2596 cells which have low NFkB expression.

      Conclusion
      Nuclear NFkB expression is a poor prognostic factor in MPM. DHMEQ, which inhibits nuclear translocation of NF-kB, inhibits cell proliferation in MPM cell lines. Furthermore, increased NF-kB expression in resistant cells suggests this pathway may play a role in development of cisplatin resistance in MPM. Inhibition of NF-kB may therefore prove to be of potential therapeutic benefit in MPM treatment and re-sensitisation of resistant MPM to cisplatin.

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