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. Crucially, they can kill cancer cells that have become resistant to PARP inhibitors – an existing treatment for patients with BRCA mutations.
Researchers are already planning to test the new drug class in upcoming clinical trials. If the trials are successful, POLQ inhibitors could enter the clinic as a new approach to treating a range of cancers with BRCA mutations, such as breast, ovarian, pancreatic and prostate cancer.
Scientists at The Institute of Cancer Research in London and the pharmaceutical company Artios explored the potential of using POLQ inhibitors in treating cancer cells with defects in the BRCA genes. In this new work, researchers have 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. Researchers also found that POLQ inhibitors work very well when used together in combination with PARP inhibitors.
Study co-leader, Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London, and Deputy Director of the Breast Cancer Now Toby Robins Research Centre at the ICR, said: “We have identified a new class of precision medicine that strips cancers of their ability to repair their DNA. This new type of treatment has the potential to be effective against cancers which already have weaknesses in their ability to repair their DNA, through defects in their BRCA genes. And excitingly, the new drugs also seem to work against cancer cells that have stopped responding to an existing treatment called PARP inhibitors – potentially opening up a new way of overcoming drug resistance. I’m very keen to see how they perform in clinical trials.”
Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said: “It’s exciting that the new POLQ inhibitors should provide a different approach to treating cancers with BRCA gene defects – and particularly that this class of drugs should retain their activity in cancers that have developed resistance to PARP inhibitors. Most exciting of all is the potential of combining POLQ and PARP inhibitor drugs to prevent the evolution of BRCA-mutant cancers into more aggressive, drug-resistant forms – a major challenge that we see in the clinic.”