For over 70 years, doctors have used 6-thioguanine (6-TG) to treat leukemia — but scientists are still uncovering why some cells succumb to it while others don't. A new study published in Nature Communications by researchers at CeMM, the University of Oxford, the Weizmann Institute of Science, and the University of Dundee has identified an unexpected player: a protein called NUDT5.

The twist? NUDT5's influence has nothing to do with its enzyme function. When researchers simply blocked the protein's enzymatic activity, cell responses to 6-TG barely changed. But when they used a cutting-edge technique called targeted protein degradation — physically removing NUDT5 from cells entirely — those cells became significantly more resistant to the drug. Genetic experiments confirmed the same result, pointing to a hidden, non-catalytic role for NUDT5 in drug sensitivity.

The study also uncovered a surprising dynamic: NUDT5 and a related protein, NUDT15, appear to push cells in opposite directions. Loss of NUDT15 makes cells more sensitive to 6-TG, while loss of NUDT5 makes them more resistant — suggesting two distinct biological levers controlling drug response.

Key Takeaways

• Blocking a protein's enzyme activity is not the same as removing the protein — and that distinction has meaningful biological consequences
• Targeted protein degradation can reveal biological functions that traditional enzyme inhibitors miss entirely
• NUDT5 and NUDT15 have opposing effects on thiopurine drug sensitivity, opening new avenues for understanding variable patient responses to leukemia treatment

Why it matters: This research reframes how scientists think about drug-protein interactions and could help explain why patients respond so differently to thiopurine therapies — an important step toward more personalized leukemia treatment strategies.