Discovering a new layer of control for a decades-old leukemia drug
For more than 70 years, the drug 6-thioguanine (6-TG) has been used to treat leukemia. Although its clinical effects have been studied extensively, scientists are still uncovering the molecular mechanisms that determine whether cells succumb to the drug or survive its attack.
For over seven decades, the leukemia drug 6-thioguanine (6-TG) has been in clinical use. Despite extensive research on its effects, scientists continue to unravel the molecular processes that determine whether cells respond to the drug or resist it. Now, a team of researchers from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, in collaboration with experts from the University of Oxford, the Weizmann Institute of Science, and the University of Dundee, have discovered an unexpected factor in this process: the protein NUDT5.
Their findings, published in the journal Nature Communications, reveal a new layer of control for 6-TG and could have significant implications for leukemia treatment. The research team initially expected NUDT5 to influence 6-TG through its enzymatic activity. However, they found that inhibiting the enzyme had little impact on the drug's effectiveness.
Instead, the researchers discovered that NUDT5 acts as a molecular scaffold, organizing cellular metabolism and influencing the drug's action through a non-enzymatic mechanism. This unexpected behavior was discovered through the development of a targeted protein degradation platform, which allowed the researchers to remove NUDT5 entirely from cells.
By comparing the effects of NUDT5 degradation with conventional NUDT5 inhibitors, the team found that degrading the protein protected cells from 6-TG's toxic effects, while inhibition of the enzyme had little impact. The study also revealed a surprising relationship between NUDT5 and another protein, NUDT15. While loss of NUDT15 increases sensitivity to 6-TG, depletion of NUDT5 makes cells more resistant to treatment.
This suggests that NUDT5 and NUDT15 operate through distinct and opposing mechanisms. The researchers emphasize that proteins can have important biological functions that are independent of their enzymatic activity. By removing NUDT5 rather than simply inhibiting it, the study uncovered a hidden layer of biology that helps determine how cells respond to 6-TG and other clinically important drugs.
Although the findings do not immediately lead to a new therapy, they open new avenues for understanding the variability in patient responses to thiopurine treatment and demonstrate the potential of targeted protein degradation to reveal hidden biological functions.
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