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The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation

Hiba Ahmad Zahreddine1, Biljana Culjkovic-Kraljacic1, Sarit Assouline2

  • 1Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, Université de Montréal, P.O. Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada.

Nature
|May 30, 2014
PubMed

Insights

Drug resistance in acute myeloid leukemia (AML) to cytarabine and ribavirin was overcome by targeting GLI1. Inhibiting GLI1, a transcription factor, prevents drug inactivation, offering a new strategy for AML treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Drug resistance is a significant challenge in acute myeloid leukemia (AML) treatment.
  • Cytarabine (Ara-C)-based therapies offer limited long-term survival for AML patients.
  • Ribavirin, an eIF4E inhibitor, showed initial promise in AML but resistance developed.

Purpose of the Study:

  • To identify mechanisms of drug resistance to ribavirin and Ara-C in AML.
  • To investigate the role of GLI1 and UGT1A in mediating this resistance.
  • To explore strategies for overcoming drug resistance in AML.

Main Methods:

  • Analysis of gene expression in resistant AML cells.
  • Investigating the functional role of GLI1 in drug metabolism.
  • Assessing the efficacy of GLI1 inhibition in preclinical models.

Main Results:

  • Elevated levels of glioma-associated protein 1 (GLI1) and UDP glucuronosyltransferase (UGT1A) enzymes were observed in resistant cells.
  • GLI1 was found to be sufficient to induce UGT1A-dependent glucuronidation of ribavirin and Ara-C, leading to drug resistance.
  • Inhibition of GLI1, either genetically or pharmacologically, restored sensitivity to ribavirin and Ara-C.

Conclusions:

  • A novel mechanism of drug resistance involving GLI1 and UGT1A in AML has been identified.
  • GLI1 plays a critical role in the inactivation of ribavirin and Ara-C through glucuronidation.
  • Targeting GLI1 presents a potential therapeutic strategy to overcome drug resistance in AML patients.

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