DHMEQ may provide a therpeutic option in targeting inflammatory mediated acquired and intrinsic cisplatin resistance in non-small cell lung cancer — ASN Events
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  3. DHMEQ may provide a therpeutic option in targeting inflammatory mediated acquired and intrinsic cisplatin resistance in non-small cell lung cancer

DHMEQ may provide a therpeutic option in targeting inflammatory mediated acquired and intrinsic cisplatin resistance in non-small cell lung cancer (#295)

Anne-Marie Baird 1 2 , Peter Godwin 2 , Susan Heavey 2 , Kazuo Umezawa 3 , Martin Barr 2 , Derek Richard 1 , Kathy Gately 2 , Kenneth O'Byrne 1 2 4
  1. Cancer and Ageing Research Program, Queensland University of Technology, Brisbane, QLD, Australia
  2. Thoracic Oncology Research Group, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
  3. Aichi Medical University, Aichi, Japan
  4. Divison of Cancer Services , Princess Alexandra Hospital, Brisbane, QLD, Australia

Aims

Cisplatin based doublet-chemotherapy is the backbone of lung cancer treatment, as the majority of patients present with advanced disease. Both inherent and acquired drug resistance are significant clinical obstacles as objective responses are observed in less than 50% of patients. The aim of this project is to characterise the role of NF-kappaB mediators in cisplatin resistant non-small cell lung cancer (NSCLC).

Methods

Cisplatin resistant (CisR) NSCLC cells were derived from original age-matched parent cells (PT) (H460/H1299/A549/SKMES-1/MOR). Basal levels of NF-kappaB mediators were examined using qPCR arrays (168 genes) and validated using RT-PCR. Proliferation assays (BrdU ELISA) were performed to assess whether the selective inhibition of NF-kappaB with DHMEQ, could re-sensitize cells to cisplatin. Comet assays (DNA damage) were also performed to determine the effect of DHMEQ alone or in combination with irradiation (6 Gy).

Results

The glucocorticoid receptor signalling pathway scored highly using Ingenuity® with 34% of differentially regulated genes involved in this pathway. Significant increases were observed in TNF and TNFSF1A with a concomitant decrease in IL-1B in the H460 cells (p<0.05, CisR vs. PT). CCL2 and CCL5 were consistently elevated throughout the entire CisR panel (p<0.05, CisR vs. PT). Simultaneous addition of DHMEQ and cisplatin augmented both PT and CisR sensitivity to cisplatin (p<0.05, DHMEQ/Cisplatin vs. cisplatin). Pre-treatment with DHMEQ further improved cisplatin sensitivity. In addition, DHMEQ enhanced the effect of irradiation in PT and CisR cells.

Conclusions

NF-kappaB pathways are de-regulated in cisplatin resistant NSCLC. Data suggests that the development of chemo-resistance may be driven in part through an up-regulation of TNF and CCL chemokines. DHMEQ may be a viable option in addressing acquired and inherent chemo-resistance given its ability to improve cisplatin sensitivity. Ultimately this project will provide novel targets for therapy and predictive biomarkers to stratify lung cancer patients to cisplatin treatment.
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