148P - Targeting NFKB in cisplatin resistant NSCLC

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Basic Science
Lung and other Thoracic Tumours
Presenter Kathy Gately
Authors K.A. Gately1, S. Heavey2, P. Godwin1, M. Barr3, K.J. O'Byrne4
  • 1Clinical Medicine, Trinity College Dublin/St James Hospital, 8 - Dublin/IE
  • 2Trinity College Dublin/St. James Hospital, 8 - Dublin/IE
  • 3Clinical Medicine, Trinity College Dublin, Dublin/IE
  • 4Hope Directorate, St James's Hospital, 8 - Dublin/IE

Abstract

The most effective systemic chemotherapy for Non Small Cell Lung Cancer (NSCLC) is cisplatin-based combination treatment. However, chemoresistance is a major therapeutic problem with the patients' tumours either de novo resistant to therapy or ultimately developing resistance to cisplatin. Understanding the mechanisms underpinning cisplatin resistance (CR) may lead to the development of predictive biomarkers and novel therapies for NSCLC and other platinum treated tumours in the future. The NF-?B pathway has been implicated in tumour initiation, progression, and resistance to chemotherapy. Although small-molecule inhibitors of NF-?B have been proposed as single-agent therapies for cancers with aberrant NF-?B activity, most classic NF-?B inhibitors are poorly selective and result in off-target effects. Dehydroxymethyl-epoxyquinomicin (DHMEQ) is an inhibitor of low molecular weight designed from the structure of the antibiotic epoxyquinomicin C. The aim of this study is to investigate the role of the PI3K-NF?B pathway in resistance to cisplatin in NSCLC and assess the effect of NF-?B inhibition by DHMEQ in cisplatin sensitive and resistant cell lines. A panel of cisplatin resistant NSCLC cell lines (H460, SKMES1, A549) were developed in our laboratory. H460 parent & resistant cell lines were screened for changes in mRNA expression using the PI3K Profiler array (SABiosciences). Changes in gene expression were validated by QPCR and protein expression by Western blot and HCA. IkBa exons 3-5 were screened for mutations by sequencing. The effect of DHMEQ (inhibitor of NF-?B translocation) was assessed by HCA assays. An 11.99 fold increase in IkBa mRNA expression was identified in the cisplatin resistant H460 cells compared to parent cells. QPCR, Western blot and HCA confirmed this overexpression of IkBa. No mutations were identified in exons 3-5 of the IkBa gene. Inhibition of NF-kB by DHMEQ led to increased apoptosis and decreased proliferation in cisplatin resistant cells versus parent cells implying NF-kB plays a significant role in cisplatin resistance. We are evaluating the synergistic effects of DHMEQ and cisplatin both in vitro and in vivo on tumour growth and spontaneous lung metastasis in athymic nude mice. DHMEQ may provide a beneficial treatment strategy for NSCLC patients who progress on cisplatin.

Disclosure

All authors have declared no conflicts of interest.