Scientists say aggressive cancers could be treated with immunotherapies that direct the immune system to kill cancer cells with specific drug resistance-causing mutations.
Drug resistance mutations that restore activity of specific genes as a way of avoiding the effects of drug treatment could leave tumours vulnerable to the effects of immunotherapy, according to a new study.
We could use immunotherapy drugs like checkpoint inhibitors to harness the body’s immune response
Study leader professor Chris Lord, deputy head of breast cancer research at the Institute of Cancer Research (ICR), London, said: “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.
“But we often noted that the way in which some cancer cells repair BRCA genes (which are important in fighting cancer) 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.
“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.”
Scientists studied cancers that had evaded the effects of platinum chemotherapies and drugs called PARP inhibitors – which are now licensed for ovarian, breast, pancreatic and prostate cancers – by repairing their BRCA genes.
They found that the new versions of the BRCA1 or BRCA2 genes were subtly different from the same genes in healthy cells.
Researchers believe the differences in these genes are big enough that it should be possible to train the body’s immune system to spot and kill cancer cells with the repaired BRCA genes.
PARP inhibitors attack cancers with BRCA gene mutations or various other genetic faults which leave them vulnerable to DNA damage.
However, cancers can sidestep the effects of PARP inhibitors or chemotherapy through genetic changes that switch the BRCA genes back on – known as reversion mutations.
The team from the CRUK Gene Function Laboratory and Breast Cancer Now Research Centre at the Institute of Cancer Research (ICR) found that some BRCA mutations were more likely than others to develop reversion mutations that restarted their gene activity.
Detecting these mutations could identify patients whose cancers might be expected to be at higher risk of developing resistance to treatment.
Where reversion mutations occurred, the team found that repaired BRCA genes created proteins which differed from normal cells.
Computer models predicted that these would often be immunogenic – meaning that the immune system would recognise them as foreign.
Professor Paul Workman, chief executive of the ICR, said: “Cancer evolution and drug resistance is the biggest challenge we face in research and treatment today. Studies like this are incredibly valuable in dissecting out how, why and when cancers can evolve resistance to current drugs.
“Excitingly, this research opens up the potential for a brand new approach to treatment that uses cancer’s defences against it, by targeting the very mutations which give the disease resistance to existing drug therapy.”
The study, published in the Cancer Discovery journal, was funded by Cancer Research UK, Breast Cancer Now and the Schottlander Research Charitable Trust.
