PARP inhibitors are a type of targeted therapy currently used to treat BRCA-mutated ovarian cancer and have been approved for treatment of advanced BRCA-mutated breast cancer in the USA.

The new research suggests that combining PARP inhibitors with some immunotherapies could offer an effective treatment for certain cancers.

A new study in lung and breast cancer cells

Some cancer cells can hide from the immune system, making them less susceptible to immunotherapies. In a new study, scientists at the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, and the Institut Gustave Roussy in France have found that PARP inhibitors could help to unmask some of these cancers and prevent them evading detection by immune cells.

The researchers studied cells from non-small cell lung cancers and triple-negative breast cancers with mutations in genes ERCC1 or BRCA respectively, which make them vulnerable to PARP inhibitors.

Treatment with PARP inhibitors led to an accumulation of broken pieces of DNA in the cancer cells, which in turn activated the tumour cells’ internal alarm system, sending out molecular signals known to attract immune cells.

Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London, who led the study, explained:

The findings of this study substantially change our understanding of how PARP inhibitors work. We now know that they not only kill tumours by damaging their DNA, but also by attracting immune cells to attack them – acting as a sort of double-pronged attack.

How do PARP inhibitors work?

PARP inhibitors can specifically kill cancer cells with faults in genes involved in DNA repair, such as the BRCA 1 and 2 genes in breast cancer, or the ERCC1 gene in some lung cancers, both of which were used in this study. 

PARP inhibitors were first developed as a cancer treatment following landmark research by UK scientists at the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London in 2005, who demonstrated for the first time that cancer cells with BRCA1 and BRCA2 mutations were very sensitive to this class of drugs.

Dr Kotryna Temcinaite, Research Communications Manager at Breast Cancer Now, which helped fund the study, said:

It’s really encouraging to see that drugs originally designed to treat BRCA-mutated breast and ovarian cancers could also be used to treat lung cancer. It shows just how vital it is that we understand exactly how a drug works, and explore new uses for it, to help drive faster progress in finding new treatment options for patients.

Breast cancer cells with faulty BRCA genes already have a compromised DNA repair system and PARP inhibitors block their remaining ability to repair DNA. This leads to cells accumulating more and more damage to their DNA until they can no longer survive. Being a targeted therapy, PARP inhibitors also have less severe side effects.

Boosting the effect of immunotherapies

Immunotherapies are making their way as a new cancer treatment. These highly targeted treatments are designed to harness the power of a patient’s own immune system to detect and kill cancer cells, and leave healthy cells unharmed – reducing the risk of difficult side-effects. 

Unfortunately, they don’t work for everyone and research is ongoing to identify which patients would benefit from immunotherapies, and to combine immunotherapies with other treatments to make them more effective.

Professor Chris Lord said:

Immunotherapy is a genuinely brilliant cancer treatment but generally only for the 10 to 20 per cent of people who respond to it. Finding the tumour is half of the battle in immunotherapy so by attracting immune cells to it, PARP inhibitors could help the treatment to work in more patients.

In the study, the researchers observed that PARP inhibitor treatment also enhanced cancer’s ability to make a molecule called PD-L1, which is known to disable immune system’s ability to launch an attack against cancer. 

Immunotherapies that block this molecule, called checkpoint inhibitors, are currently being trialled as breast cancer treatment in patients whose tumours have high levels of PD-L1 – but using PARP inhibitors to enhance these PD-L1 levels could provide another approach to help make checkpoint inhibitor treatment suitable for more patients.

Dr Kotryna Temcinaite, Research Communications Manager at Breast Cancer Now, welcomed further research in this area:

Activating the immune system to attack tumours is an exciting approach that is beginning to show promise in breast cancer. We now look forward to seeing how the combination of PARP inhibitors and checkpoint inhibitors may work in clinical trials for breast cancer patients.

The research was published in The Journal of Clinical Investigation and was funded by Breast Cancer Now and Cancer Research UK.