- People who inherit a mutated BRCA gene have an increased risk of some types of breast, ovarian, pancreatic, and prostate cancer.
- In laboratory-based experiments using animals and organoids, a new class of drug that prevents the repair of damaged DNA killed cancer cells that had BRCA mutations. Importantly, healthy cells were unharmed.
- The drugs also killed cells that had become resistant to an existing type of anticancer therapy.
- The next step will be to test the new drugs on humans in clinical trials.
The molecular blueprint of life, DNA, is vulnerable to damage that can scramble the vital information that it encodes.
If a cell fails to repair these genetic errors as they occur, the mutations eventually cause its death. Occasionally, however, mutations can facilitate the uncontrolled cell replication that is cancer.
One of the inbuilt DNA repair mechanisms that human cells use to fix errors is overseen by two genes, called BRCA1 and BRCA2.
If a person inherits a mutated copy of either gene, their impaired ability to repair DNA can lead to cancer, including certain types of breast, ovarian, pancreatic, and prostate cancer.
In the mid-1990s, scientists discovered that they could kill these cancers with drugs called poly-ADP ribose polymerase (PARP) inhibitors, which switch off another DNA repair mechanism.
The research revealed that while a persistent, low rate of uncorrected DNA errors can eventually cause cancer, a high rate of uncorrected errors — as a result two or more impaired repair mechanisms — quickly kills the cells.
As a result, PARP inhibitors have proved to be effective. However, cancerous cells can develop resistance to them in the course of treatment.
Another problem is that when the drugs are combined with chemotherapy, the resulting side effects limit the dosages that people can tolerate.
The good news is that scientists have found a potential solution to both these problems. They may be on the brink of developing a whole new class of anticancer drugs, called POLQ inhibitors, which target yet another tool in cells’ DNA repair kit.
“All cells have to be able to repair damage to their DNA to stay healthy — otherwise, mutations build up and eventually kill them. We have identified a new class of precision medicine that strips cancers of their ability to repair their DNA,” says co-senior author of the study Chris Lord, Ph.D., a professor of cancer genomics at The Institute of Cancer Research, in London.
“This new type of treatment has the potential to be effective against cancers that already have weaknesses in their ability to repair their DNA, through defects in their BRCA genes,” he adds.
The research was a collaboration between the institute and the pharmaceutical company Artios.
In experiments involving animal models of the disease and cancer organoids, three-dimensional mini-tumors grown in a lab, the scientists showed that the drugs can kill cancerous cells that have a BRCA mutation.
Crucially, the new drugs appeared to leave healthy cells unharmed. The researchers are therefore hopeful that POLQ inhibitors will cause fewer side effects than their predecessors.
“As a targeted treatment, we hope that POLQ inhibitors could be a kinder alternative, with less side effects than current treatment options,” says Simon Vincent, Ph.D., director of research at the charity Breast Cancer Now, which helped fund the study.
The scientists also showed that POLQ inhibitors can kill cells that have become resistant to PARP inhibitors. Alternately, by giving people with new cancer diagnoses a combination of the drugs, doctors may be able to prevent resistance from developing in the first place.
“Drug resistance is a major hurdle that we must tackle to stop women dying from breast cancer, so it is also exciting that POLQ inhibitors offer a hope of overcoming resistance, in some cases,” says Dr. Vincent.
The research has been published in
POLQ is a gene that makes a protein called POLθ, which repairs a particular kind of damage to DNA.
The new anticancer drugs work by preventing the protein from doing its job, which kills cells that also have a mutated BRCA gene.
As Michelle Mitchell, chief executive officer of the charity Cancer Research UK, which also helped fund the study, explains:
“By revisiting weaknesses in the BRCA repair pathway, researchers have not only found a way to make PARP inhibitors more effective, but they may have also identified an entirely new class of targeted drugs for BRCA cancers, which could include pancreatic cancer, which has limited treated options. We look forward to seeing if these promising results in the lab transfer into benefits for patients when tested in trials.”
The authors of the new study speculate that POLQ inhibitors may cause fewer side effects than PARP inhibitors when combined with chemotherapy drugs, which are designed to kill cancer cells by damaging their DNA.
However, only clinical trials will reveal whether this and the other potential benefits of the new drugs can be realized in humans.