ATR inhibitors – so what do you do?
Inside most cells in our body is our DNA, which contains the instructions that tell cells what to do and how to behave. DNA is constantly being damaged, but our cells are usually able to fix any faults, thanks to something called the DNA Damage Response. This enables the cell to repair its damage, or alternatively, if there’s too much damage it can hit the ‘self-destruct’ button, removing itself from the body so it doesn’t cause any problems.
In cancer cells, the DNA Damage Response can go into overdrive. Cancer therapies like chemotherapy and radiotherapy work by trying to cause as much damage to the cancer cells’ DNA as possible. Also, certain faults inside cancer cells can make them very dependent on the DNA Damage Response just to survive, let alone patching up DNA.
One of the main actors in the DNA Damage Response is a protein called ATR – specifically, ATR is part of a surveillance team, looking out for DNA damage and calling the DNA repair cavalry if needed. Blocking ATR with drugs called ATR inhibitors, and so hampering the DNA Damage Response, could therefore be an effective way to treat cancer – the cancer cells would accumulate so much damage that they can’t function at all and will ultimately die.
Several ATR inhibitor drugs are currently in development, and some are already in early clinical trials. Researchers believe that they could be used on their own or in combination with chemotherapy drugs. But in order to turn these drugs into an effective treatment for people with breast cancer, we first need a way to figure out who would most benefit from ATR inhibitors.
Dr Chris Lord and his team at the Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research in London think they have found a way to do just that.
ATR inhibitors, meet ARID1A
In a study published recently in the journal Nature Communications, funded by Cancer Research UK and Breast Cancer Now, the researchers started by looking for any genes which, when switched off, might increase the effectiveness of ATR inhibitors. Looking at over 1,200 different genes, they found that blocking a gene called ARID1A makes breast cancer cells more susceptible to ATR inhibitors.
ARID1A is part of a group of proteins which model something called chromatin, the name given to DNA when it’s packed up with other molecules so that a whole metre’s worth of DNA can be squeezed inside one tiny cell. Faults in the genes for ARID1A and its chromatin remodelling family are common in cancer, present in around 20% of tumours.
Investigating further, the researchers found that three ATR inhibitor drugs were much more effective against breast cancer cells grown in the lab which had the ARID1A gene “switched off” (and so couldn’t produce any ARID1A), compared to those which had the ARID1A gene. The research team then replicated similar results in other types of cancer, and ATR inhibitors were much better at slowing the growth of bowel and ovarian tumours in mice if the cells in these tumours had faults in the ARID1A gene.
Dr Lord and colleagues are excited about these results because they mean that ATR inhibitors could benefit more patients than previously thought. This is partly because mutations in the genes for ARID1A and other proteins it works closely with are relatively common across different types of cancer; for example, whilst ARID1A mutations are present in about 2-3% of breast cancers, they occur in 45% of clear-cell ovarian cancer, and a large number of stomach, bladder, and liver cancers.
The next step would be to test the findings of this study in cancer patients to understand whether it really works in practice, and Dr Lord hopes to set up a clinical trial within a couple of years to do this.
We’re getting a deeper understanding of the genes that go wrong in breast cancer, through studies like the one earlier this year which gave us the most complete map of the disease to date. Dr Lord’s research is a great example of how we could match up a new generation of treatments to take advantage of these mutations.
Whilst drugs like ATR inhibitors aren’t likely to benefit everyone with breast cancer, the upside is that they could be very effective for some people, which would mean a much more favourable balance between the benefit of these drugs versus side-effects that they could cause.
By funding research like Dr Lord’s, Breast Cancer Now is working towards a future where every patient can expect to have one or more drugs that can be matched with their particular breast cancer, based upon the mutations or other features of their tumour. These highly specific treatments could be used alongside more ‘traditional’ therapies which benefit larger groups of patients.
Ultimately, it would mean that every breast cancer patient gets the ‘tailored’ treatment programme that’s most effective against their tumour, so giving a better chance of survival for everyone with the disease.
Breast Cancer Now’s support of Dr Chris Lord’s research was funded by Stand Up To Cancer.