New drug class for cancers with faulty BRCA genes

Friday June 18th 2021

A new class of targeted cancer drugs could treat patients whose tumours have faulty copies of the BRCA cancer genes, British researchers have reported.

Scientists at The Institute of Cancer Research, London, and the pharmaceutical company Artios, explored the potential of POLQ inhibitors in treating cancer cells with defects in the BRCA genes.

Their study, published in Nature Communications, has identified prototype drugs that not only stop the protein POLQ from working, but which also kill cancer cells with BRCA gene mutations.

It is already known that genetically removing POLQ kills cells with BRCA gene defects, although no drugs that prevent POLQ from working had been identified.

In this new study, the researchers identified prototype drugs that both stop POLQ from working and kill cancer cells with BRCA gene mutations.

When cells were treated with POLQ inhibitors, cancer cells with BRCA gene mutations were no longer able to repair their DNA and died, but this did not happen in normal cells. The team says it means POLQ inhibitors could offer a treatment for cancer with few side effects.

The POLQ inhibitors were also found to work well with PARP inhibitors, which could be used at a lower dose.

In laboratory tests in rats and in organoids, POLQ inhibitors shrunk BRCA-mutant cancers that had stopped responding to PARP inhibitors because of a defect in the Shieldins. This suggests POLQ inhibitors could offer an alternative treatment where PARP inhibitors are no longer working, the researchers say.

Study co-leader Professor Chris Lord, professor of cancer genomics at The Institute of Cancer Research, London, 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, added: “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.”

Nature Communications 17 June 2021

Tags: Cancer | Genetics | Pharmaceuticals | UK News | Women's Health & Gynaecology

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