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Nature. 2014 Jul 3;511(7507):90-3. doi: 10.1038/nature13283. Epub 2014 May 28.

The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation.

Author information

1
Institute 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.
2
Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montréal, Québec H3T 1E2, Canada.
3
Pharmascience Inc., 6111 Royalmount Avenue, Montreal, Quebec H4P 2T4, Canada.
4
1] Pharmascience Inc., 6111 Royalmount Avenue, Montreal, Quebec H4P 2T4, Canada [2] JAQJAM Consulting, Montreal J7V 9B6, Canada.
5
Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 1305 York Avenue, New York, New York 10021, USA.
6
Hôpital Maisonneuve-Rosemont, 5415 Boulevard de l'Assomption, Montréal, Québec H1T 2M4, Canada.
7
McMaster University/Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
8
Department of Medicine, Division of Hematology/Oncology, 601 Elmwood Avenue, University of Rochester, Rochester, New York 14627, USA.
9
Division of Hematology, Department of Medicine, University of Colorado Denver, 13123 East 16th Avenue, Aurora, Colorado 80045, USA.

Abstract

Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of months. Therapies are under development to improve outcomes and include targeting the eukaryotic translation initiation factor (eIF4E) with its inhibitor ribavirin. In a Phase II clinical trial in poor prognosis AML, ribavirin monotherapy yielded promising responses including remissions; however, all patients relapsed. Here we identify a novel form of drug resistance to ribavirin and Ara-C. We observe that the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacological inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.

PMID:
24870236
PMCID:
PMC4138053
DOI:
10.1038/nature13283
[Indexed for MEDLINE]
Free PMC Article
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