A cancer drug currently being tested in patients may have entered clinical trials on the basis of an incorrect understanding of how it works. That is the conclusion of a study led by the University of Sydney with collaborators at Goethe University, the University of Oxford and the Institute of Cancer Research in London, published in Nature Chemical Biology.
The work examined the experimental drug zavondemstat and the closely related research compound QC6352, developed for cancers including colorectal, pancreatic and prostate tumours. Both were designed and described as inhibitors of KDM4, a protein family that can help cancer cells grow and spread when overactive. Instead, the researchers found, both compounds largely work by blocking DHODH — an enzyme cancer cells rely on to produce the building blocks of DNA.
'We can think of DHODH as a machine producing the bricks needed to build new DNA. If you switch off the machine, the cell starts running out of bricks and can no longer efficiently copy its DNA and keep dividing,' said lead author Professor Lenka Munoz of the University of Sydney's Charles Perkins Centre.
The discrepancy surfaced when the team tested the compounds as a possible repurposed treatment for glioblastoma, the most common and aggressive form of brain cancer. Other KDM4 inhibitors failed to reproduce the anti-cancer effects seen with QC6352 — a result that would be unexpected if KDM4 were the real driver. Using patient-derived glioblastoma stem cells, tumour models and a series of genetic and molecular experiments, the researchers traced the response to DHODH rather than KDM4.
The implications reach well beyond one molecule. Laboratories around the world have used QC6352 as a leading tool to study KDM4 biology, so the interpretation of that literature may need revisiting, and the clinical development of zavondemstat now rests on a different mechanism than assumed. 'Our study shows this is not just a historical problem but one still happening today,' Munoz said. 'Greater rigour is needed to ensure we understand exactly how potential treatments work before they move into clinical testing.'
The finding also points to an opportunity: DHODH inhibition emerges as a possible new avenue for glioblastoma, and several DHODH-targeting drugs are already being investigated in other cancers. The team additionally developed new compounds that inhibit KDM4 without touching DHODH, giving researchers cleaner tools to study what KDM4 actually does.
