Sonic Hedgehog Factor GLI1 Induces Resistance to Cytarabine and Ribavirin in AML via Glucuronidation

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Responses to cytarabine-based therapy in acute myeloid leukemia (AML) are often of short duration. Ribavirin has been used to inhibit the eukaryotic translation initiation factor (eIF4E) and has produced responses, including remissions, in AML, but relapse invariably occurs.

As reported in Nature, Zahreddine and colleagues identified a new form of drug resistance to cytarabine and ribavirin. They found that levels of the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the uridine diphosphate glucuronosyltransferase (UGT1A) family of enzymes—which add glucuronic acid to drugs and modify their activity in numerous tissues—were elevated in cytarabine- and ribavirin-resistant cells.

Studies in animal models showed that increased GLI1 alone was sufficient to induce UGT1A-dependent glucuronidation of cytarabine and ribavirin and to result in resistance to the drugs. Genetic or pharmacologic inhibition of GLI1 prevented such resistance, indicating a potential strategy to overcome drug resistance in some patients. ■

Zahreddine HA, et al: Nature 511:90-93, 2014.




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