Elucidating inflammatory meditated mechanisms of intrinsic and acquired chemo-resistance in non-small cell lung cancer  — ASN Events
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Elucidating inflammatory meditated mechanisms of intrinsic and acquired chemo-resistance in non-small cell lung cancer  (#171)

Anne-Marie Baird 1 2 , Sarah-Louise Ryan 1 3 , Peter Godwin 2 , Susan Heavey 2 , Kazuo Umezawa 4 , Martin Barr 2 , Steven Gray 2 , Anthony Davies 3 , Derek Richard 1 , Kathy Gately 2 , Kenneth J O'Byrne 1 2 3 5
  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. Translational Cell Imaging Queensland , Queensland University of Technology, Woolloongabba, QLD, Australia
  4. Aichi Medical University, Aichi, Japan
  5. Divison of Cancer Services , Princess Alexandra Hospital, Brisbane, QLD, Australia

Aims:

Cisplatin based doublet-chemotherapy is commonly used in non-small cell lung cancer (NSCLC) treatment with an initial objective response rate of 40-50%. However, intrinsic and acquired chemo-resistance constitutes a major clinical obstacle. The mechanisms of resistance have yet to be fully understood. We have previously demonstrated that NF-κB levels are elevated in cisplatin resistant cells (CisR) and that the use of an NF-κB inhibitor, DHMEQ, resulted in greater CisR cell death. The goal of this project is to elucidate the mechanistic links between NF-κB regulated pathways and the development of cisplatin resistant NSCLC.

Methods:

The expression of NF-κB mediators and immune regulators were assessed in an isogenic NSCLC cell line model of cisplatin resistance using qPCR arrays (252 genes). A number of targets were identified and validated using PCR. The effect of drug combinations (Cisplatin and DHMEQ) was also determined. Comet assays (DNA damage) were also performed to determine the effect of DHMEQ alone or in combination with irradiation (6 Gy).

Results:

Various chemokines and their receptors were elevated in cisplatin resistant (CisR) cells compared with cisplatin sensitive (PT). In addition, a number of key TLRs and regulators of the innate immune pathway were altered. DHMEQ enhanced cellular sensitivity to cisplatin in both PT and CisR cell lines (p<0.05). This drug also overcame the chemo-protective effect of a number of chemokines and enhanced irradiation induced DNA damage. An animal study will commence shortly using DHMEQ alone and in combination with cisplatin.

Conclusions:

Immune-modulators such as DHMEQ may be a novel viable option in addressing inflammatory mediated acquired and intrinsic NSCLC chemo-resistance. In addition, immune regulators identified in this project may provide innovative targets for immuno-oncology therapy.  

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