Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC

Objectives: The majority of patients with non-small cell lung cancer (NSCLC) present with advanced stage disease, at which time chemotherapy is usually the most common treatment option. While somewhat effective, patients treated with platinum-based regimens will eventually develop resistance, with others presenting with intrinsic resistance. Multiple pathways have been implicated in chemo-resistance, however the critical underlying mechanisms have yet to be elucidated. The aim of this project was to determine the role of inflammatory mediators in cisplatin-resistance in NSCLC. Materials and methods: Inflammatory mediator, NF-kappa B, and its associated pathways were investigated in an isogenic model of cisplatin-resistant NSCLC using age-matched parental (PT) and corresponding cisplatin-resistant (CisR) sublines. Pathways were assessed using mass spectrometry, western blot analysis and qRT-PCR. The cisplatin sensitizing potential of an NF-kappa B small molecule inhibitor, DHMEQ, was also assessed by means of viability assays and western blot analysis. Results: Proteomic analysis identified dysregulated NF-kappa B responsive targets in CisR cells when compared to PT cells, with increased NF-kappa B expression identified in four out of the five NSCLC sub-types examined (CisR versus PT). DHMEQ treatment resulted in reduced NF-kappa B expression in the presence of cisplatin, and re-sensitized CisR cells to the cytotoxic effects of the drug. Conclusion: This study identified NF-kappa B as a potential therapeutic target in cisplatin-resistant NSCLC. Furthermore, inhibition of NF-kappa B using DHMEQ re-sensitized chemo-resistant cells to cisplatin treatment.