What role does NFkB play in chemoresistance?

This was one of the very first research questions I ever set out to answer, way back as a final year undergraduate in Trinity College Dublin, in 2010/2011.

Since then, over many years, a few papers, and with an ever expanding global team, it has remained at least a side project (and in some cases a driving interest) for some of my oldest friends in research!

For me, it began with my final year thesis project, which involved comparing a panel chemosensitive and chemoresistant lung cancer cell lines, developed by Dr Martin Barr as a tool to investigate response to chemotherapy.

We wanted to understand how lung tumours develop resistance to chemotherapy over time, so that we could find better ways to treat them!

We screened the cell lines using qPCR arrays, and identified a few potential genes of interest including NFKBIA, which is involved in regulating NFkB.

NFkB is a well studied transcription factor that seems to play a flexible and complex role in many biological processes.

This initial finding caught the eye of my project supervisor Dr Kathy Gately, who immediately began to wonder if NFkB could be a potential therapeutic target in chemoresistant lung cancer. The project ended up winning the Margaret Ciotti medal as the highest marked thesis in the School, and with the excitement of a new finding (and this early recognition boosting my confidence), it was an easy decision to stick around in Dr Gately’s lab to begin my PhD.

While the PhD project itself was focused more upstream on PI3K/AKT/mTOR, we did further develop our NFkB finding, and it ended up becoming both my first research paper and the first chapter of my PhD thesis. In this work, we used a drug called DHMEQ, which is an inhibitor of NFkB translocation developed by a Japanese collaborator, and we found that it was more effective in treating chemoresistant lung cells than chemosensitive ones.

I have fond memories of this work, as I got to try out a range of new molecular techniques for the first time, including the obligatory ones like cell culture, drug treatments, qPCR and Western blotting, but also things like high content immunofluorescence imaging, proliferation and apoptosis assays, and I even got to run some Sanger sequencing on a machine named ‘Spongebob’!

https://www.tandfonline.com/doi/pdf/10.4161/cbt.29841

It was clear from the data that this work opened up a whole range of possibilities, and it was time to expand. My colleagues Peter Godwin and Dr Anne-Marie Baird each took aspects of this forward, with Peter publishing a great review on the topic that remains the most highly cited paper on my Google Scholar profile (thanks Peter!) and Anne-Marie being awarded a fellowship from the International Association for the Study of Lung Cancer to investigate a new take on the work down in Brisbane, Australia.

https://www.frontiersin.org/articles/10.3389/fonc.2013.00120/full

Anne-Marie’s work (alongside Dr Sarah-Louise Ryan) brought a fresh and exciting angle, interrogating the role of inflammatory pathways in NFkB mediated cisplatin resistance, as well as confirming that the NFkB translocation inhibitor wasn’t just more effective in chemoresistant cells, but in fact could be used to resensitise those cells to the effects of the chemotherapy itself.

https://www.sciencedirect.com/science/article/pii/S016950021930529X

So where are we now?

Well, we’re certainly not the only ones investigating NFkB in chemoresistance…

With groups all over the world also teasing out the role that NFkB is playing in this setting, things are becoming increasingly clear, and also increasingly complex.

It turns out NFkB is quite a promiscuous player in cancer development and aggresivity!

With seemingly endless feedback loops, regulation and cross-talk with other pathways, it seems to have the capacity to drive wide ranging and even opposing phenotypes. Equally, it often appears to be a mere passenger, caught up in attempts at cell survival during times of stress.

With these flexible abilities, can we truly say that NFkB itself is a viable target for drug development?

Sadly, probably not.

But we do hope that our growing understanding of the role that it plays in chemoresistance will help us to identify better targets that work alongside it, and ultimately better ways to treat these tumours.

As ever, we keep searching.

Big thanks to Kathy, Anne-Marie, Martin, Peter and Sarah-Louise, as well as all the other researchers involved in these projects!

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