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GLI1-Inducible Glucuronidation Targets a Broad Spectrum of Drugs

Hiba Ahmad Zahreddine1, Biljana Culjkovic-Kraljacic1, Jadwiga Gasiorek1

  • 1Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology , Université de Montréal , Montréal , Quebec , Canada.

ACS Chemical Biology
|February 15, 2019
PubMed

Insights

Glioma-associated protein 1 (GLI1) drives broad drug resistance in cancer by increasing glucuronidation enzymes. This pathway, involving calreticulin, offers a potential target for overcoming multidrug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cancer drug resistance is a major clinical challenge.
  • Previously identified GLI1-mediated resistance to specific leukemia drugs via UGT1A enzymes.

Purpose of the Study:

  • To investigate the broad spectrum of GLI1-induced drug resistance.
  • To elucidate the mechanism of GLI1-mediated resistance.
  • To identify potential therapeutic vulnerabilities in resistant cells.

Main Methods:

  • Assessed GLI1's effect on resistance to a panel of compounds.
  • Investigated the role of calreticulin in GLI1-mediated resistance.
  • Examined the sensitivity of resistant cells to ATP inhibitors.

Main Results:

  • GLI1 confers resistance to approximately 40 compounds, including methotrexate and venetoclax.
  • Calreticulin is essential for GLI1-induced resistance.
  • Resistant cancer cells exhibit increased sensitivity to ATP inhibitors.

Conclusions:

  • GLI1-inducible glucuronidation represents a broad-spectrum multidrug resistance pathway.
  • Calreticulin is a key mediator in this resistance mechanism.
  • Targeting ATP pathways may overcome GLI1-driven drug resistance.

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