Targeting four-stranded DNA could improve ovarian cancer treatment

Four-stranded regions of the genome have been linked to chemotherapy resistance in ovarian cancer, offering a new potential avenue for therapy.

While the majority of the genome exists in double-stranded helix form, it can also adopt alternative configurations. These were initially considered to be quirks of biology, but increasingly, research has uncovered that they are involved in regulating gene expression. A new collaborative study, led by researchers at Imperial College London, focused on the four-stranded 'G-quadruplex' configuration, known to be more enriched in cancer cells (see BioNews 1079 and 1127). The researchers investigated the presence of G-quadruplexes in ovarian cancer cells grown in a dish before exposing them to chemotherapy to induce resistance. They observed that G-quadruplexes were strongly enriched in the resistant cells, and appeared to help activate genes that counteract chemotherapy.

'Our findings show resistance isn't solely driven by changes in the DNA sequence but can also arise from changes to the unique three-dimensional shapes DNA forms,' said Dr Jenna Robinson, lead author of the study published in Genome Biology. 'This creates a new therapeutic opportunity which may be very fruitful.'

The researchers also found that by targeting the G-quadruplex structures with specialised drugs, they were able to resensitise the resistant cells, restoring their vulnerability to chemotherapy.

Women with ovarian cancer often respond well to chemotherapy initially, but in 70 percent of cases the cancer returns and becomes increasingly drug-resistant with repeated courses. Therefore, one of the major barriers to treatment is not chemotherapy being ineffective, but the subsequent reappearance of tumours and their ability to become resistant to it. This research raises the possibility that using similar drugs in ovarian cancer patients could reduce chemotherapy resistance.

'This is an exciting discovery. For over a decade, we've known that G-quadruplex DNA can form in the genome, but this is the first time we've observed a functional response linked to targeting these structures – one that could be harnessed for therapeutic applications,' said Dr Marco Di Antonio, one of the study leads. 'With top ovarian cancer specialists at Imperial just down the road, we can now fast-track investigating if these promising results can benefit patients.'

However, this approach has not yet been tested in living humans, and it remains to be seen whether the drugs would have the same effect or whether G-quadruplexes play the same role that they did in isolated cells.

The findings are limited to ovarian cancer, and the team plans to conduct further research to explore whether the same structures aid chemotherapy resistance in other cancers.