Scientists have identified a new class of targeted cancer drugs that offer the potential to treat patients whose tumours have faulty copies of the BRCA cancer genes.
The drugs, known as POLQ inhibitors, specifically kill cancer cells with mutations in the BRCA genes while leaving healthy cells unharmed.
And crucially, they can kill cancer cells that have become resistant to PARP inhibitors – an existing treatment for patients with BRCA mutations.
Researchers are planning to test the new drug class in clinical trials. If the trials are successful, POLQ inhibitors could become a treatment for a range of cancers with BRCA mutations, such as breast, ovarian, pancreatic and prostate cancer.
The study by scientists at The Institute of Cancer Research, London, and the pharmaceutical company Artios, is published in Nature Communications.
For some time now, scientists have known that genetically removing a protein known as POLQ killed cells with BRCA gene defects, although drugs that prevent POLQ from working had not been identified.
In this new work, the researchers identified prototype drugs that not only stop POLQ from working, but which also kill cancer cells with BRCA gene mutations.
Both BRCA genes and POLQ are involved in repairing DNA. Cancer cells can survive without one or other of them, but if both are blocked or their genes switched off, cancer cells can no longer repair their DNA and they die.
Researchers found that when cells were treated with POLQ inhibitors, cancer cells with BRCA gene mutations were stripped of their ability to repair their DNA and died, but normal cells did not. By killing cancer cells with BRCA gene mutations, while leaving normal cells unharmed, POLQ inhibitors could offer a treatment for cancer with relatively few side effects.
The researchers also found that POLQ inhibitors work very well when used together in combination with PARP inhibitors.
The addition of POLQ inhibitors meant that PARP inhibitors were effective when used at a lower dose. And in laboratory tests in rats and in organoids – three-dimensional mini-tumours grown in the lab – POLQ inhibitors were able to shrink BRCA-mutant cancers that had stopped responding to PARP inhibitors because of a defect in a set of genes known as the ‘Shieldins’
This suggests that POLQ inhibitors could offer an alternative treatment where PARP inhibitors are no longer working. Researchers believe that using a POLQ inhibitor in combination with a PARP inhibitor in patients with cancers that have faulty BRCA genes could prevent resistance from emerging in the first place.
Scientists at The Institute of Cancer Research (ICR), funded by Breast Cancer Now and Cancer Research UK, discovered how to genetically target PARP inhibitors against BRCA-mutant cancers and, with colleagues at The Royal Marsden NHS Foundation Trust, helped run clinical trials leading to the first PARP inhibitor being approved for use.