A new class of drugs could treat a series of cancers with defective BRCA genes

MADRID, 18 Jun. (EUROPA PRESS) –

Scientists have identified a new class of anticancer drugs that offer the potential to treat patients whose tumors have defective copies of the BRCA cancer genes. These drugs, known as POLQ inhibitors, specifically kill cancer cells with mutations in the BRCA genes, leaving healthy cells intact.

Most importantly, they can kill cancer cells that have become resistant to PARP inhibitors, an existing treatment for patients with BRCA mutations, according to the researchers in the journal Nature Communications.

Researchers are already planning to test this new class of drugs in upcoming clinical trials. If the trials are successful, POLQ inhibitors could enter the clinic as a new approach to treating a number of cancers with BRCA mutations, such as breast, ovarian, pancreas and prostate.

Scientists from the London Cancer Research Institute and the pharmaceutical company Artios have studied the potential of POLQ inhibitors to treat cancer cells with defects in the BRCA genes.

Scientists have known for some time that the genetic deletion of a protein known as POLQ killed cells with defects in the BRCA genes, although no drugs had been identified that would prevent POLQ from working.

In this new work, the researchers identified prototype drugs that not only prevent POLQ from working, but also kill cancer cells with BRCA gene mutations.

Both the BRCA and POLQ genes are involved in DNA repair. Cancer cells can survive without one or the other, but if both are blocked or their genes are turned off, cancer cells can no longer repair their DNA and die.

The researchers found that when cells were treated with POLQ inhibitors, cancer cells with mutations in the BRCA gene lost their ability to repair their DNA and died, but normal cells did not. By killing cancer cells with BRCA gene mutations and leaving normal cells unscathed, POLQ inhibitors could offer a cancer treatment with relatively few side effects.

The researchers also found that POLQ inhibitors work very well when used in combination with PARP inhibitors.

The addition of the POLQ inhibitors meant that the PARP inhibitors were effective when used at a lower dose. And in laboratory tests performed on rats and organoids – three-dimensional minitumors grown in the laboratory – POLQ inhibitors were able to reduce BRCA-mutated cancers that had stopped responding to PARP inhibitors due to a defect in a set of genes known as ‘Shieldins’.

This suggests that POLQ inhibitors could offer an alternative treatment when PARP inhibitors no longer work. Researchers believe that using a POLQ inhibitor in combination with a PARP inhibitor in patients with cancers with defective BRCA genes could prevent the emergence of resistance in the first place.

Scientists at the Institute for Cancer Research (ICR), funded by Breast Cancer Now and Cancer Research UK, discovered how to genetically target PARP inhibitors against BRCA-mutated cancers and, together with colleagues from The Royal Marsden NHS Foundation Trust, helped to conduct the clinical trials that led to the approval of the first PARP inhibitor. The next step will be to test POLQ inhibitors in clinical trials led by Artios.

Study co-director Professor Chris Lord, Professor of Cancer Genomics at the London Cancer Research Institute and Deputy Director of the Toby Robins Breast Cancer Research Center at the ICR, explains that “all cells have to be capable of repairing the damage to their DNA to stay healthy, otherwise the mutations accumulate and end up killing them. “

“We have identified a new class of precision medicine that deprives cancers of their ability to repair DNA,” he notes. “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. “

And, what is more interesting – he concludes -, the new drugs also seem to work against cancer cells that have stopped responding to an existing treatment, PARP inhibitors, which could open a new path to overcome resistance to drugs. I’m looking forward to seeing how they work in clinical trials. “

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