CANCER RESEARCH UK scientists have shown that a class of experimental drug treatments already in clinical trials could also help the body’s immune system to fight cancer, according to a study published today (Thursday) in the journal Cell.*
Scientists at the University of Edinburgh revealed that a protein called Focal Adhesion Kinase, or FAK – which is often overproduced in tumours - enables cancer cells to elude attacks by the immune system.
FAK usually sends signals to help healthy cells to grow and move around.
But the researchers discovered it plays a different role in cancer cells, changing the nature of the immune system so that it protects the cancer cells rather than destroying them.
They then showed that using an experimental FAK inhibitor** prevented this change in the immune system allowing the cancer cells to be treated as a threat.
This is the first time that FAK inhibitors have been shown to influence the immune system, and particularly whether or not it recognises and fights cancer. This provides an unexpected and exciting potential new use for existing FAK inhibitor drugs.
The research was carried out in mice with a form of skin cancer called squamous cell carcinoma, but is likely to also apply to other cancers. The results showed that tumours completely disappeared when the mice were given FAK inhibitors.
This research was funded by Cancer Research UK, European Research Council, and the Medical Research Council.
Dr Alan Serrels, one of the lead authors, at the Edinburgh Cancer Research UK Centre at the University of Edinburgh, said: “FAK is hi-jacked by cancer cells to protect them from the immune system. This exciting research reveals that by blocking FAK, we’ve now found a promising new way to help the immune system recognise the cancer and fight it.
“The drug in this study is already in early stage clinical trials and could potentially be an excellent complement to existing immunotherapy treatments. Because it works within tumour cells rather than influencing the immune cells directly, it could offer a way to reduce the side effects of treatments that harness the power of the immune system against cancer.”
Nell Barrie, senior science communications manager at Cancer Research UK, said: “This promising research suggests these drugs may be able to help the immune system to destroy cancer cells.
“Research to maximise the power of the immune system is a really exciting area that Cancer Research UK scientists are exploring in detail. This particular approach hasn’t yet been tested in people, but there are plans to now find out how it could benefit patients alongside other immunotherapy treatments.”
When a protein is shown to have the ability to catalyse a chemical reaction – i.e. to act as an enzyme, the assumption is often made that this is what its biological function is. Scientists from the MRC Human Genetics Unit have shown that this assumption can be wrong. They have shown that RING1B, a protein required for embryonic development in mammals, is able to fulfil many of its biological functions even in the absence of its ability to act as an enzyme.
Gastrulation is a very early phase of embryo development during which the three principle tissue types of the adult are generated. Central to this process is a family of gene repressors, collectively known as polycomb proteins. Deficiency of RING1B, a core component of this regulatory system, prevents mouse embryos from completing gastrulation. At the molecular level, RING1B remodels chromatin, both via direct chemical modification and by mechanical compaction. However, until now, which of these functions is essential for early embryonic development was unknown.
To address this question, Illingworth and colleagues engineered mouse embryonic stem cells to expresses a stable, but catalytically inactivate, form of RING1B. Cells carrying this mutation had near normal gene expression, despite lacking the ability to chemically modify chromatin. Mouse embryos derived from these RING1B mutant cells were able to complete gastrulation and to continue apparently quite normal development until much later in embryogenesis. These findings suggest that the catalytic activity of RING1B is largely dispensable for early mammalian development.
“Our findings highlight the importance of dissecting out enzymatic versus structural roles when trying to understand the function of essential proteins”
Doctor Robert Illingworth, MRC Human Genetics Unit, IGMM
The study is published in the journal Genes and Development and was funded by the Medical Research Council.
Illingworth RS, Moffat M, Mann AR, Read D, Hunter CJ, Pradeepa MM, Adams IR, Bickmore WA. Genes Dev. 2015 Sep 15;29(18):1897-902. doi: 10.1101/gad.268151.115.