PUBLISHED ON: 22 July 2020

Study has suggested that immunotherapy could be effective against some cancers with changes in BRCA genes that become resistant to treatment.

two female researchers sitting at a desk in a laboratory

Tackling drug resistance

New research, partly funded by Breast Cancer Now, found that cancers that became resistant to drugs by restoring the function of BRCA1 or BRCA2 genes could be vulnerable to immunotherapy.

Scientists at the Institute of Cancer Research, London studied breast, ovarian, pancreatic and prostate cancers with altered BRCA1 or BRCA2 genes. They wanted to understand how these cancers become resistant to treatment by repairing the BRCA genes.

They found the repaired versions of these genes were subtly different from the same genes in healthy cells and could lead to cancer cells being recognisable to the body’s immune system.

Treating cancers with altered BRCA genes

Cancers with changes in BRCA genes could be treated with platinum chemotherapy, such as carboplatin, or PARP inhibitors. Both treatments rely on alterations in BRCA genes to work well.

However, cancers can sometimes sidestep the effects of these treatments through genetic changes that restore the function of BRCA genes.

Professor Chris Lord, who led the study, added: ‘Cancers that have repaired their BRCA mutations are difficult to treat, as their cells have recovered some of the properties of normal cells – in many ways this means that there are no obvious vulnerabilities to target.’

To understand how we could treat these cancers that had become resistant, researchers studied every reported incident of drug resistance linked to mutations restoring the BRCA function.

Finding alternative treatments

Researchers found that some types of BRCA mutation were more likely than others to be reversed to escape treatment. Detecting these mutations could identify patients whose cancers might be at higher risk of developing resistance to PARP inhibitors or platinum chemotherapy.

The team found that the repaired BRCA genes created proteins which differed from those created in normal cells. Computer models predicted that the immune system could recognise them as foreign.

‘We often noted that the way in which some cancer cells repair BRCA genes means that the proteins that they make are not completely normal, and could be recognised by the immune system as foreign, opening up ways to target and treat these cancers by using the immune system,’ explained Chris.

It means that immunotherapies that take the brakes off the immune system could be effective against these cancers. It may even be possible to generate an immune response against the reverted BRCA proteins using a vaccine, if the reversions can be accurately predicted.

Future directions

‘We could use immunotherapy drugs like checkpoint inhibitors to harness the body’s immune response, and direct it at reversion mutations. That has the potential to open up an exciting new avenue of treatment for patients with aggressive cancers that are resistant to the best available current drugs,’ said Chris.

Researchers now want to study more cases where BRCA function is turned back on to escape the effects of treatment to confirm these findings.

The research was published in the journal Cancer Discovery and funded by Cancer Research UK, Breast Cancer Now and the Schottlander Trust.

 

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