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Europe PMC team

 | 6 November 2013


Another brick in the wall

By Ian Le Guillou (University of Cambridge, UK)
Awarded joint 2nd prize for Access to Understanding 2013

A mutation that allows cells to grow out of
control could also provide a new way to target and destroy cancer cells. This
potential Achilles’ heel comes from a mutation in a gene called PTEN, which is found in a wide range of

PTEN is one of many tumour suppressor genes that we have to prevent our
cells from growing out of control. If the PTEN gene stops working because of a
mutation, it can cause tumours to develop – indeed many tumours have a mutated
form of PTEN. However when a door
closes, a window opens: the PTEN mutation helps the tumour to grow, but
it could also mark it out as a target.

3D-rendered illustration of cancer cells
Shutterstock Image ID: 159517493 Copyright: xrender

Researchers from the Institute of Cancer Research, London, found that
switching off another gene known as NLK killed
tumour cells that had the PTEN mutation. This makes NLK
a good target for drug developers to create a new cancer treatment.

The difficult thing about cancer is that it is made of us – our own cells
mutate and grow wildly out control. That means it is unlikely there will ever
be a quick fix. Antibiotics work efficiently because bacteria are so different
to us that we can develop drugs that target their weaknesses yet barely affect
our own cells. But how do you kill something that is the same as you? Current
treatments for cancer cause a lot of side-effects in patients because as they
try to kill the cancer they also do damage everything else in the body. This is
why finding ways to target cancer specifically is so important.

There are several proteins in our cells which we cannot live without, and
if the genes responsible for producing those proteins are mutated or switched
off the cells die. Targeting these proteins and genes are rarely going to be
useful for treatments, as they will kill the patient about as quickly as they
kill the cancer. So Alan Ashworth and colleagues set out to find proteins that
are not essential in healthy cells, but cells with the PTEN mutation cannot
live without. This would pave the way for designing drugs that target the
tumour and leave healthy cells alone.

The researchers took samples of tumour cells with and without the mutation,
and switched off genes for important proteins that are used for regulating lots
of processes in the cell. To do this they used small molecules of RNA (DNA’s
less famous cousin) which interfere with the processes of specific genes. This
is why these molecules are known as small interfering RNA (or siRNA). They
block the chain of events that allow a gene to produce a protein, effectively
switching it off. By switching off 779 genes individually, they could look for
ones where cells with the PTEN mutation died and cells without the
mutation survived.

Dividing cancer cells
Shutterstock Image ID: 158445182 Copyright: Juan Gaertner

This is how the researchers discovered the powerful effect of switching off
the NLK gene. They are not certain how this works but it appears to
protect a protein called FOXO1 that can act as a backup tumour suppressor and
cause the cancer cell to die. When PTEN is mutated, the FOXO1 protein becomes
vulnerable to a process called phosphorylation, which means it is ejected from
the cell nucleus and destroyed. NLK is one of the proteins that phosphorylates
FOXO1 and so by switching off the NLK gene,
FOXO1 is able to do its job.

This is just the start of a long journey from the lab to (potentially) the
hospital. The researchers have shown that targeting NLK is more likely to
kill mutated cells than normal cells, but that does not mean it is safe. NLK
still has a role to play in healthy cells and preventing it from working is
likely to have side-effects, but it could be worthwhile if this approach can
kill tumours. The next stage is to develop a drug to stop the NLK protein from
working, so that it can be tested further in cells and in living organisms.

Promising leads against cancer appear often, yet very few ever make it as
treatments. One big hurdle is making it through clinical trials; the new drug
has to be better than currently available treatments. Targeting NLK
would only work against cancers with the PTEN mutation, but now we can use the
mutation as a marker to find out which patients that applies to. We are now in
the age of personalised medicine, where we can have 100 different treatments for
100 different people with 100 different cancers. Gradually, we are finding ways
to attack cancer in whichever form it appears and build up our range of
treatments. The weaknesses that we find are not going to cure all cancers but
each one provides another brick in the wall.

This entry describes research published in the following article, selected by Breakthrough breast cancer:

PMCID: PMC3483146
Ana M. Mendes-Pereira, Christopher J. Lord, and Alan

PLoS One
2012) 7(10)

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2013 there were 9 articles to choose from, selected by the Europe PMC funders.

The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for announcements about the competition.

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