The problematic morning sickness drug thalidomide caused birth defects in thousands of children during the 1950s. The compound was recently repurposed as an anticancer treatment, and progress has been made to understand its therapeutic actions, but how it led to developmental defects decades ago remains unclear. Now, a team led by Eric Fischer of Dana-Farber Cancer Institute has evidence that thalidomide might induce teratogenicity by interacting with a key protein in its anticancer mechanism (eLife, DOI: 10.7554/eLife.38430).
Previous research found that thalidomide produces anticancer effects by binding to cereblon, a component of an enzyme known as a ubiquitin ligase, which is involved in marking proteins for degradation. In the current study, Fischer’s team identified a potential binding target of the thalidomide-cereblon complex that might contribute to the compound’s teratogenic actions. In a proteomics screen in human embryonic stem cells, thalidomide degraded a transcription factor called SALL4. In humans, mutations of SALL4 lead to a limb deformation syndrome that resembles thalidomide-induced birth defects. Researchers have suspected SALL4 has a role in thalidomide’s pathogenesis, but this is the first time experimental evidence supports that hypothesis, Fischer says. He adds that though the evidence suggests SALL4 is a major target in thalidomide-induced birth defects, there could be other targets and combined effects of multiple targets at play. His lab plans to perform animal studies to further examine the mechanism.
Neil Vargesson at the University of Aberdeen, a developmental biologist who has published research on thalidomide’s mechanisms, says that the paper is “a step forward” in identifying what happens next after thalidomide binds to cereblon, and the findings have the potential to explain the drug’s teratogenic actions. But he adds that the researchers would need to validate their findings in animal embryos to show this interaction does result in “the huge range and variability of damage” seen in the clinical setting. “Just how thalidomide-induced loss of SALL4 causes the damage and whether other targets are also needed remains to be fully determined,” he says.