Researchers from King's have identified a new way to treat certain blood cancers using existing drugs, by turning a once-dismissed part of our DNA into a therapeutic target.
The study, published in Blood, focused on myelodysplastic syndrome (MDS) and chronic lymphocytic leukemia (CLL). These cancers often have mutations in two key genes, ASXL1 and EZH2, which normally control the activity of other genes by switching them on or off. When these genes are damaged, cells lose control of their ability to create new cells, resulting in abnormal cell growth.
Most cancer treatments work by blocking the functions of harmful proteins made by faulty genes. However, if the protein is missing entirely as it is with these mutations, there is nothing for the drugs to block, leaving patients with limited treatment options and worse outcomes.
Nearly half of human DNA is made up of repetitive sequences called transposable elements (TEs), once thought to be useless 'junk DNA'. The researchers found that in cancers with damaged ASXL1 and EZH2 genes, TEs become unusually active. This overactivity stresses the cancer cells and damages their DNA, creating a weakness that can be turned into a treatment opportunity.
PARP inhibitors are drugs already used to treat some other cancers. They usually work by preventing cancer cells from repairing damaged DNA. In this study, they acted differently. When TEs move around in the genome, they cause breaks in the DNA that are however protected by PARP proteins for repair. Blocking PARP prevents this repair, causing damage to build up until the cancer cells die.
To confirm this new mechanism, the researchers used reverse transcriptase inhibitors, which stop TEs from copying themselves. This removed the effect of PARP inhibitors, showing that the drugs were working through a unique TE-related pathway rather than their usual role in BRCA-related cancers.
This discovery offers new hope for patients with hard-to-treat cancers, by using existing drugs in a completely new way, turning what was once thought to be useless DNA into a powerful target for treatment."
Professor Chi Wai Eric So, King's College London
While this research focused on the blood cancers MDS and CLL, the findings suggest that other cancers with similar gene mutations might also be vulnerable to this approach, potentially widening the use of PARP inhibitors in cancer treatment.
