Potential new approach identified for treating BRCA-related cancers

A new class of drug could effectively treat types of breast, ovarian and prostate cancer.

Called POLQ inhibitors, the newly identified drugs specifically target cancer cells with a faulty copy of the BRCA1 orBRCA2 genes, while leaving healthy cells unharmed. Importantly, the drugs are effective against cancers that have grown resistant to other treatments - potentially offering new hope for patients with BRCA-mutatedcancers.

'All cells have to be able to repair damage to their DNA to stay healthy – otherwise mutations build up and eventually kill them,' said study co-leader Professor Chris Lord, from the Institute of Cancer Research (ICR), London. '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.'

The research focused on tumours which harbour a faulty inherited copy of either BRCA gene. Both POLQ and BRCA genes encode proteins involved in DNA repair, but at least one of these must function for a cell to survive. As a result, cancer cells with a faulty BRCA gene are especially sensitive to the blocking of POLQ. After screening over 165,000 chemical compounds, the research team were able to identify several molecules that inhibited POLQ function.

In the study, the addition of POLQ inhibitors in vitro killed BRCA-mutant cancer cells, but not healthy cells. POLQ inhibitors were also effective in rat models which had stopped responding to PARP inhibitors and caused their tumours to shrink. PARP inhibitors are currently used to treat patients with BRCA-mutant cancers, but a significant proportion of tumours can develop resistance.

The team also hope to use their findings to prevent BRCA-mutant cancers from evolving drug resistance in the first place, by treating patients with two types of drug at once.

'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,' said the ICR's chief executive, Professor Paul Workman.

Published in Nature Communications, the study was a collaboration between the ICR and Artios Pharma, Cambridge. Clinical trials are expected to begin by the end of the year.