title: The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation.
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.
authors.affiliation: 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.
authors.forename: Hiba Ahmad
authors.initials: HA
authors.lastname: Zahreddine
authors.affiliation: 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.
authors.forename: Biljana
authors.initials: B
authors.lastname: Culjkovic-Kraljacic
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montréal, Québec H3T 1E2, Canada.
authors.forename: Sarit
authors.initials: S
authors.lastname: Assouline
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gendron
authors.affiliation: Pharmascience Inc., 6111 Royalmount Avenue, Montreal, Quebec H4P 2T4, Canada.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Romeo
authors.affiliation: Pharmascience Inc., 6111 Royalmount Avenue, Montreal, Quebec H4P 2T4, Canada.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Morris
authors.affiliation: 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.
authors.forename: Gregory
authors.initials: G
authors.lastname: Cormack
authors.affiliation: 1] Pharmascience Inc., 6111 Royalmount Avenue, Montreal, Quebec H4P 2T4, Canada [2] JAQJAM Consulting, Montreal J7V 9B6, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Jaquith
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 1305 York Avenue, New York, New York 10021, USA.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montréal, Québec H3T 1E2, Canada.
authors.forename: Eftihia
authors.initials: E
authors.lastname: Cocolakis
authors.affiliation: 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.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Amri
authors.affiliation: Hôpital Maisonneuve-Rosemont, 5415 Boulevard de l'Assomption, Montréal, Québec H1T 2M4, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Bergeron
authors.affiliation: McMaster University/Hamilton Health Sciences, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, 601 Elmwood Avenue, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Division of Hematology, Department of Medicine, University of Colorado Denver, 13123 East 16th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Pei
authors.affiliation: Division of Hematology, Department of Medicine, University of Colorado Denver, 13123 East 16th Avenue, Aurora, Colorado 80045, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montréal, Québec H3T 1E2, Canada.
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.affiliation: 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.
authors.forename: Katherine L B
authors.initials: KL
authors.lastname: Borden
mesh_terms: D045744:Cell Line, Tumor; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D020723:Glucuronic Acid / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D012254:Ribavirin / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D003561:Cytarabine; D012254:Ribavirin; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase